Статті в журналах: "Small Molecular Organic Ligands"

1

Nilsson, K. Peter R. "Small organic probes as amyloid specific ligands - Past and recent molecular scaffolds." FEBS Letters 583, no. 16 (April 17, 2009): 2593–99. http://dx.doi.org/10.1016/j.febslet.2009.04.016.

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2

Polowin, Joel, Robert Poe та Michael C. Baird. "Extensions of the applicability of the MMX molecular modelling system to determination of barriers to rotation of π-bonded ligands". Canadian Journal of Chemistry 73, № 7 (1 липня 1995): 1078–83. http://dx.doi.org/10.1139/v95-133.

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The commercially available molecular mechanics package PCMODEL, which has been shown to be very useful for determining conformational energy profiles for rotation of σ-bonded ligands, cannot be utilized to determine barriers to rotation of π-bonded ligands because of limitations in the way the π-bonding interactions are defined. This paper describes a partially successful modification of the dihedral driver of PCMODEL that makes possible reasonable calculations of the conformational energy profiles for rotation of the π-bonded arene ligands in the compounds (η6-arene)Cr(CO)2(PPh3) (arene = C6H6, C6Me6) and of the π-bonded ethylene ligands in [PtCl3(η2-CH2=CH2)]− and [(η5-C5H5)Re(NO)(PPh3)(η2-CH2=CH2)]+. The steric barriers to ethylene rotation in the latter two complexes were found to be small relative to the electronic barriers to ligand rotation. Keywords: molecular mechanics, olefin rotation, conformational energy profile.

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3

Milanesi, Eva, Paola Costantini, Alberto Gambalunga, Raffaele Colonna, Valeria Petronilli, Anna Cabrelle, Gianpietro Semenzato, Andrea M. Cesura, Emmanuel Pinard, and Paolo Bernardi. "The Mitochondrial Effects of Small Organic Ligands of BCL-2." Journal of Biological Chemistry 281, no. 15 (February 14, 2006): 10066–72. http://dx.doi.org/10.1074/jbc.m513708200.

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4

Norel, R., H. J. Wolfson, and R. Nussinov. "Small Molecule Recognition: Solid Angles Surface Representation and Molecular Shape Complementarity." Combinatorial Chemistry & High Throughput Screening 2, no. 4 (August 1999): 223–36. http://dx.doi.org/10.2174/1386207302666220204193837.

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Abstract: Here we examine the recognition of small molecules by their protein and DNA receptors. We focus on two questions: First, how well does the solid angle molecular surface representation perform in fitting together the surfaces of small ligands, such as drugs and cofactors to their corresponding receptors; And second, in particular, to what extent does the shape complementarity play a role in the matching (recognition) process of such small molecules. Both questions have been investigated in protein-protein binding: "Critical Points" based on solid angle calculations have been shown to perform well in the matching of large protein molecules. They are robust, may be few in numbers, and capture satisfactorily the molecular shape. Shape complementarity has been shown to be a critical factor in protein protein recognition, but has not been examined in drug-receptor recognition. To probe these questions, here we dock 185 receptor-small ligand molecule pairs. We find that such a representation performs adequately for the smaller ligands too, and that shape complementarity is also observed. These issues are important, given the large databases of drugs that routinely have to be scanned to find candidate, lead compounds. We have been able to carry out such large scale docking experiments owing to our efficient, computer-vision based docking algorithms. Its fast CPU matching times, on the order of minutes on a PC, allows such large scale docking experiments.

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5

Peterson, Leif. "Small Molecule Docking of DNA Repair Proteins Associated with Cancer Survival Following PCNA Metagene Adjustment: A Potential Novel Class of Repair Inhibitors." Molecules 24, no. 3 (February 12, 2019): 645. http://dx.doi.org/10.3390/molecules24030645.

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Natural and synthetic small molecules from the NCI Developmental Therapeutics Program (DTP) were employed in molecular dynamics-based docking with DNA repair proteins whose RNA-Seq based expression was associated with overall cancer survival (OS) after adjustment for the PCNA metagene. The compounds employed were required to elicit a sensitive response (vs. resistance) in more than half of the cell lines tested for each cancer. Methodological approaches included peptide sequence alignments and homology modeling for 3D protein structure determination, ligand preparation, docking, toxicity and ADME prediction. Docking was performed for unique lists of DNA repair proteins which predict OS for AML, cancers of the breast, lung, colon, and ovaries, GBM, melanoma, and renal papillary cancer. Results indicate hundreds of drug-like and lead-like ligands with best-pose binding energies less than −6 kcal/mol. Ligand solubility for the top 20 drug-like hits approached lower bounds, while lipophilicity was acceptable. Most ligands were also blood-brain barrier permeable with high intestinal absorption rates. While the majority of ligands lacked positive prediction for HERG channel blockage and Ames carcinogenicity, there was a considerable variation for predicted fathead minnow, honey bee, and Tetrahymena pyriformis toxicity. The computational results suggest the potential for new targets and mechanisms of repair inhibition and can be directly employed for in vitro and in vivo confirmatory laboratory experiments to identify new targets of therapy for cancer survival.

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6

Schwarz, Benjamin, and Carsten Streb. "Architectural control of urea in supramolecular 1D strontium vanadium oxide chains." Dalton Transactions 44, no. 9 (2015): 4195–99. http://dx.doi.org/10.1039/c4dt03691c.

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7

Tatikonda, Rajendhraprasad, Evgeny Bulatov, Zülal Özdemir, Nonappa Nonappa, and Matti Haukka. "Infinite coordination polymer networks: metallogelation of aminopyridine conjugates and in situ silver nanoparticle formation." Soft Matter 15, no. 3 (2019): 442–51. http://dx.doi.org/10.1039/c8sm02006j.

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Self-assembly of silver(i) and low molecular weight organic ligands derived from aminopyridine conjugates led to in situ generation of an infinite coordination polymer network and ultra small nanoparticles.

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8

Cho, Yeon-Jin, Sun-Hye Choi, Rami Lee, Hongik Hwang, Hyewhon Rhim, Ik-Hyun Cho, Hyoung-Chun Kim, Jeong-Ik Lee, Sung-Hee Hwang, and Seung-Yeol Nah. "Ginseng Gintonin Contains Ligands for GPR40 and GPR55." Molecules 25, no. 5 (March 2, 2020): 1102. http://dx.doi.org/10.3390/molecules25051102.

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Gintonin, a novel ginseng-derived glycolipoprotein complex, has an exogenous ligand for lysophosphatidic acid (LPA) receptors. However, recent lipid analysis of gintonin has shown that gintonin also contains other bioactive lipids besides LPAs, including linoleic acid and lysophosphatidylinositol (LPI). Linoleic acid, a free fatty acid, and LPI are known as ligands for the G-protein coupled receptors (GPCR), GPR40, and GPR55, respectively. We, herein, investigated whether gintonin could serve as a ligand for GPR40 and GPR55, using the insulin-secreting beta cell-derived cell line INS-1 and the human prostate cancer cell line PC-3, respectively. Gintonin dose-dependently enhanced insulin secretion from INS-1 cells. Gintonin-stimulated insulin secretion was partially inhibited by a GPR40 receptor antagonist but not an LPA1/3 receptor antagonist and was down-regulated by small interfering RNA (siRNA) against GPR40. Gintonin dose-dependently induced [Ca2+]i transients and Ca2+-dependent cell migration in PC-3 cells. Gintonin actions in PC-3 cells were attenuated by pretreatment with a GPR55 antagonist and an LPA1/3 receptor antagonist or by down-regulating GPR55 with siRNA. Taken together, these results demonstrated that gintonin-mediated insulin secretion by INS-1 cells and PC-3 cell migration were regulated by the respective activation of GPR40 and GPR55 receptors. These findings indicated that gintonin could function as a ligand for both receptors. Finally, we demonstrated that gintonin contained two more GPCR ligands, in addition to that for LPA receptors. Gintonin, with its multiple GPCR ligands, might provide the molecular basis for the multiple pharmacological actions of ginseng.

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9

Comess, Kenneth M., Mark E. Schurdak, Martin J. Voorbach, Michael Coen, Jonathan D. Trumbull, Houjun Yang, Lan Gao, et al. "An Ultraefficient Affinity-Based High-Throughout Screening Process: Application to Bacterial Cell Wall Biosynthesis Enzyme MurF." Journal of Biomolecular Screening 11, no. 7 (September 14, 2006): 743–54. http://dx.doi.org/10.1177/1087057106289971.

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The authors describe the discovery of a new class of inhibitors to an essential Streptococcus pneumoniae cell wall biosyn-thesis enzyme, MurF, by a novel affinity screening method. The strategy involved screening very large mixtures of diverse small organic molecules against the protein target on the basis of equilibrium binding, followed by iterative ultrafiltration steps and ligand identification by mass spectrometry. Hits from any affinity-based screening method often can be relatively nonselective ligands, sometimes referred to as “nuisance” or “promiscuous” compounds. Ligands selective in their binding affinity for the MurF target were readily identified through electronic subtraction of an empirically determined subset of promiscuous compounds in the library without subsequent selectivity panels. The complete strategy for discovery and identification of novel specific ligands can be applied to all soluble protein targets and a wide variety of ligand libraries.

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10

Shahroz, Mir Mohammad, Hemant Kumar Sharma, Abdulmalik S. A. Altamimi, Mubarak A. Alamri, Abuzer Ali, Amena Ali, Safar Alqahtani, et al. "Novel and Potential Small Molecule Scaffolds as DYRK1A Inhibitors by Integrated Molecular Docking-Based Virtual Screening and Dynamics Simulation Study." Molecules 27, no. 4 (February 9, 2022): 1159. http://dx.doi.org/10.3390/molecules27041159.

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The dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a novel, promising and emerging biological target for therapeutic intervention in neurodegenerative diseases, especially in Alzheimer’s disease (AD). The molMall database, comprising rare, diverse and unique compounds, was explored for molecular docking-based virtual screening against the DYRK1A protein, in order to find out potential inhibitors. Ligands exhibiting hydrogen bond interactions with key amino acid residues such as Ile165, Lys188 (catalytic), Glu239 (gk+1), Leu241 (gk+3), Ser242, Asn244, and Asp307, of the target protein, were considered potential ligands. Hydrogen bond interactions with Leu241 (gk+3) were considered key determinants for the selection. High scoring structures were also docked by Glide XP docking in the active sites of twelve DYRK1A related protein kinases, viz. DYRK1B, DYRK2, CDK5/p25, CK1, CLK1, CLK3, GSK3β, MAPK2, MAPK10, PIM1, PKA, and PKCα, in order to find selective DYRK1A inhibitors. MM/GBSA binding free energies of selected ligand–protein complexes were also calculated in order to remove false positive hits. Physicochemical and pharmacokinetic properties of the selected six hit ligands were also computed and related with the proposed limits for orally active CNS drugs. The computational toxicity webserver ProTox-II was used to predict the toxicity profile of selected six hits (molmall IDs 9539, 11352, 15938, 19037, 21830 and 21878). The selected six docked ligand–protein systems were exposed to 100 ns molecular dynamics (MD) simulations to validate their mechanism of interactions and stability in the ATP pocket of human DYRK1A kinase. All six ligands were found to be stable in the ATP binding pocket of DYRK1A kinase.

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11

Scodeller, Pablo, and Eliana K. Asciutto. "Targeting Tumors Using Peptides." Molecules 25, no. 4 (February 13, 2020): 808. http://dx.doi.org/10.3390/molecules25040808.

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To penetrate solid tumors, low molecular weight (Mw < 10 KDa) compounds have an edge over antibodies: their higher penetration because of their small size. Because of the dense stroma and high interstitial fluid pressure of solid tumors, the penetration of higher Mw compounds is unfavored and being small thus becomes an advantage. This review covers a wide range of peptidic ligands—linear, cyclic, macrocyclic and cyclotidic peptides—to target tumors: We describe the main tools to identify peptides experimentally, such as phage display, and the possible chemical modifications to enhance the properties of the identified peptides. We also review in silico identification of peptides and the most salient non-peptidic ligands in clinical stages. We later focus the attention on the current validated ligands available to target different tumor compartments: blood vessels, extracelullar matrix, and tumor associated macrophages. The clinical advances and failures of these ligands and their therapeutic conjugates will be discussed. We aim to present the reader with the state-of-the-art in targeting tumors, by using low Mw molecules, and the tools to identify new ligands.

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12

SCRUTTON, Nigel S., та Andrew R. C. RAINE. "Cation-π bonding and amino-aromatic interactions in the biomolecular recognition of substituted ammonium ligands". Biochemical Journal 319, № 1 (1 жовтня 1996): 1–8. http://dx.doi.org/10.1042/bj3190001.

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Cation-π bonds and amino-aromatic interactions are known to be important contributors to protein architecture and stability, and their role in ligand-protein interactions has also been reported. Many biologically active amines contain substituted ammonium moieties, and cation-π bonding and amino-aromatic interactions often enable these molecules to associate with proteins. The role of organic cation-π bonding and amino-aromatic interactions in the recognition of small-molecule amines and peptides by proteins is an important topic for those involved in structure-based drug design, and although the number of structures determined for proteins displaying these interactions is small, general features are beginning to emerge. This review explores the role of cation-π bonding and amino-aromatic interactions in the biological molecular recognition of amine ligands. Perspectives on the design of ammonium-ligand-binding sites are also discussed.

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13

Kaneti, Jose, Vanya Kurteva, Milena Georgieva, Natalia Krasteva, George Miloshev, Nadezhda Tabakova, Zhanina Petkova, and Snezhana M. Bakalova. "Small Heterocyclic Ligands as Anticancer Agents: QSAR with a Model G-Quadruplex." Molecules 27, no. 21 (November 4, 2022): 7577. http://dx.doi.org/10.3390/molecules27217577.

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G-quadruplexes (GQs) have become valid targets for anticancer studies in recent decades due to their multifaceted biological function. Herewith, we aim to quantify interactions of potential heterocyclic ligands (Ls) with model GQs. For seven 4-aminoquinazolines and three 2-heteroaryl perimidines, seven of this ten-membered group so far unknown, we use routine quantum chemical modeling. As shown in the literature, a preferred mode of interaction of heterocycles with cellular structures is stacking to exposable faces of G-quadruplexes. To exploit the energy of this interaction as a molecular descriptor and achieve the necessary chemical precision, we use state of the art large-scale density functional theory (DFT) calculations of stacked heterocycles to a GQ. Actually, the GQ has been simplified for the computation by stripping it off all pentose phosphate residues into a naked model of stacked guanine quartets. The described model thus becomes computable. The obtained heterocyclic ligand GQ.L stacking energies, that is, their GQ affinities, are the necessary ligand descriptors. Using the ligand biological inhibitory activities (IC50) on a human malignant melanoma A375 cell line, we obtain a good linear relationship between computed ligand stacking affinities to GQ, and experimental log (IC50) values. Based on the latter relationship, we discuss a putative mechanism of anticancer activity of heterocyclic ligands via stacking interactions with GQs and thereby controlling cell regulatory activity. This mechanism may tentatively be applied to other condensed five- and six-membered small heterocycles as well.

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14

Huang, Rui, David C. Luther, Xianzhi Zhang, Aarohi Gupta, Samantha A. Tufts, and Vincent M. Rotello. "Engineering the Interface between Inorganic Nanoparticles and Biological Systems through Ligand Design." Nanomaterials 11, no. 4 (April 13, 2021): 1001. http://dx.doi.org/10.3390/nano11041001.

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Nanoparticles (NPs) provide multipurpose platforms for a wide range of biological applications. These applications are enabled through molecular design of surface coverages, modulating NP interactions with biosystems. In this review, we highlight approaches to functionalize nanoparticles with “small” organic ligands (Mw < 1000), providing insight into how organic synthesis can be used to engineer NPs for nanobiology and nanomedicine.

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15

Kim, Hyeon Jin, Mi Suk Jeong, and Se Bok Jang. "Molecular Characteristics of RAGE and Advances in Small-Molecule Inhibitors." International Journal of Molecular Sciences 22, no. 13 (June 27, 2021): 6904. http://dx.doi.org/10.3390/ijms22136904.

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Receptor for advanced glycation end-products (RAGE) is a member of the immunoglobulin superfamily. RAGE binds and mediates cellular responses to a range of DAMPs (damage-associated molecular pattern molecules), such as AGEs, HMGB1, and S100/calgranulins, and as an innate immune sensor, can recognize microbial PAMPs (pathogen-associated molecular pattern molecules), including bacterial LPS, bacterial DNA, and viral and parasitic proteins. RAGE and its ligands stimulate the activations of diverse pathways, such as p38MAPK, ERK1/2, Cdc42/Rac, and JNK, and trigger cascades of diverse signaling events that are involved in a wide spectrum of diseases, including diabetes mellitus, inflammatory, vascular and neurodegenerative diseases, atherothrombosis, and cancer. Thus, the targeted inhibition of RAGE or its ligands is considered an important strategy for the treatment of cancer and chronic inflammatory diseases.

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16

Moreno, Maria João, Luís M. S. Loura, Jorge Martins, Armindo Salvador, and Adrian Velazquez-Campoy. "Analysis of the Equilibrium Distribution of Ligands in Heterogeneous Media–Approaches and Pitfalls." International Journal of Molecular Sciences 23, no. 17 (August 28, 2022): 9757. http://dx.doi.org/10.3390/ijms23179757.

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The equilibrium distribution of small molecules (ligands) between binding agents in heterogeneous media is an important property that determines their activity. Heterogeneous systems containing proteins and lipid membranes are particularly relevant due to their prevalence in biological systems, and their importance to ligand distribution, which, in turn, is crucial to ligand’s availability and biological activity. In this work, we review several approaches and formalisms for the analysis of the equilibrium distribution of ligands in the presence of proteins, lipid membranes, or both. Special attention is given to common pitfalls in the analysis, with the establishment of the validity limits for the distinct approaches. Due to its widespread use, special attention is given to the characterization of ligand binding through the analysis of Stern–Volmer plots of protein fluorescence quenching. Systems of increasing complexity are considered, from proteins with single to multiple binding sites, from ligands interacting with proteins only to biomembranes containing lipid bilayers and membrane proteins. A new formalism is proposed, in which ligand binding is treated as a partition process, while considering the saturation of protein binding sites. This formalism is particularly useful for the characterization of interaction with membrane proteins.

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17

Blalock, J. E. "On the evolution of ligands: did peptides functionally precede metals and small organic molecules?" Cellular and Molecular Life Sciences (CMLS) 55, no. 4 (April 1, 1999): 513–18. http://dx.doi.org/10.1007/s000180050309.

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18

Reiner, Thomas, Sarah Earley, Anna Turetsky, and Ralph Weissleder. "Bioorthogonal Small-Molecule Ligands for PARP1 Imaging in Living Cells." ChemBioChem 11, no. 17 (October 21, 2010): 2374–77. http://dx.doi.org/10.1002/cbic.201000477.

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19

Kropacheva, Nadezhda O., Arseniy A. Golyshkin, Mariya A. Vorobyeva, and Mariya I. Meschaninova. "Convenient Solid-Phase Attachment of Small-Molecule Ligands to Oligonucleotides via a Biodegradable Acid-Labile P-N-Bond." Molecules 28, no. 4 (February 16, 2023): 1904. http://dx.doi.org/10.3390/molecules28041904.

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One of the key problems in the design of therapeutic and diagnostic oligonucleotides is the attachment of small-molecule ligands for targeted deliveries in such a manner that provides the controlled release of the oligonucleotide at a certain moment. Here, we propose a novel, convenient approach for attaching ligands to the 5′-end of the oligonucleotide via biodegradable, acid-labile phosphoramide linkage. The method includes the activation of the 5′-terminal phosphate of the fully protected, support-bound oligonucleotide, followed by interaction with a ligand bearing the primary amino group. This technique is simple to perform, allows for forcing the reaction to completion by adding excess soluble reactant, eliminates the problem of the limited solubility of reagents, and affords the possibility of using different solvents, including water/organic media. We demonstrated the advantages of this approach by synthesizing and characterizing a wide variety of oligonucleotide 5′-conjugates with different ligands, such as cholesterol, aliphatic oleylamine, and p-anisic acid. The developed method suits different types of oligonucleotides (deoxyribo-, 2′-O-methylribo-, ribo-, and others).

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20

Maity, Sanhita, Ravi Kumar Gundampati, and Thallapuranam Krishnaswamy Suresh Kumar. "NMR Methods to Characterize Protein-Ligand Interactions." Natural Product Communications 14, no. 5 (May 1, 2019): 1934578X1984929. http://dx.doi.org/10.1177/1934578x19849296.

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Structural information pertaining to the interactions between biological macromolecules and ligands is of potential significance for understanding of molecular mechanisms in key biological processes. Recently, nuclear magnetic resonance (NMR) spectroscopic techniques has come of age and has widened its scope to characterize binding interactions of small molecules with biological macromolecules especially, proteins. NMR spectroscopy-based techniques are versatile due to their ability to examine weak binding interactions and for rapid screening the binding affinities of ligands with proteins at atomic resolution. In this review, we provide a broad overview of some of the important NMR approaches to investigate interactions of small organic molecules with proteins.

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21

Tassinari, Martina, Alberto Lena, Elena Butovskaya, Valentina Pirota, Matteo Nadai, Mauro Freccero, Filippo Doria, and Sara Richter. "A Fragment-Based Approach for the Development of G-Quadruplex Ligands: Role of the Amidoxime Moiety." Molecules 23, no. 8 (July 27, 2018): 1874. http://dx.doi.org/10.3390/molecules23081874.

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G-quadruplex (G4) nucleic acid structures have been reported to be involved in several human pathologies, including cancer, neurodegenerative disorders and infectious diseases; however, G4 targeting compounds still need implementation in terms of drug-like properties and selectivity in order to reach the clinical use. So far, G4 ligands have been mainly identified through high-throughput screening methods or design of molecules with pre-set features. Here, we describe the development of new heterocyclic ligands through a fragment-based drug discovery (FBDD) approach. The ligands were designed against the major G4 present in the long terminal repeat (LTR) promoter region of the human immunodeficiency virus-1 (HIV-1), the stabilization of which has been shown to suppress viral gene expression and replication. Our method is based on the generation of molecular fragment small libraries, screened against the target to further elaborate them into lead compounds. We screened 150 small molecules, composed by structurally and chemically different fragments, selected from commercially available and in-house compounds; synthetic elaboration yielded several G4 ligands and two final G4 binders, both embedding an amidoxime moiety; one of these two compounds showed preferential binding for the HIV-1 LTR G4. This work presents the discovery of a novel potential pharmacophore and highlights the possibility to apply a fragment-based approach to develop G4 ligands with unexpected chemical features.

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22

Wijtmans, Maikel, Dennis Verzijl, Rob Leurs, Iwan J. P. de Esch, and Martine J Smit. "Towards Small-Molecule CXCR3 Ligands with Clinical Potential." ChemMedChem 3, no. 6 (June 16, 2008): 861–72. http://dx.doi.org/10.1002/cmdc.200700365.

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23

Majid, Mohd Faridzuan, Hayyiratul Fatimah Mohd Zaid, Muhammad Fadhlullah Abd Shukur, Azizan Ahmad, and Khairulazhar Jumbri. "Host–Guest Interactions of Zirconium-Based Metal–Organic Framework with Ionic Liquid." Molecules 28, no. 6 (March 21, 2023): 2833. http://dx.doi.org/10.3390/molecules28062833.

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A metal–organic framework (MOF) is a three-dimensional crystalline compound made from organic ligands and metals. The cross-linkage between organic ligands and metals creates a network of coordination polymers containing adjustable voids with a high total surface area. This special feature of MOF made it possible to form a host–guest interaction with small molecules, such as ionic liquid (IL), which can alter the phase behavior and improve the performance in battery applications. The molecular interactions of MOF and IL are, however, hard to understand due to the limited number of computational studies. In this study, the structural parameters of a zirconium-based metal–organic framework (UiO-66) and 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide, [EMIM][TFSI] were investigated via a combined experimental and computational approach using the linker model approach. When IL was loaded, the bond length and bond angle of organic linkers were distorted due to the increased electron density surrounding the framework. The increase in molecular orbital energy after confining IL stabilized the structure of this hybrid system. The molecular interactions study revealed that the combination of UiO-66 and [EMIM][TFSI] could be a promising candidate as an electrolyte material in an energy storage system.

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24

Gómez-Santacana, Xavier, Sabrina M. de Munnik, Tamara A. M. Mocking, Niels J. Hauwert, Shanliang Sun, Prashanna Vijayachandran, Iwan J. P. de Esch, Henry F. Vischer, Maikel Wijtmans, and Rob Leurs. "A toolbox of molecular photoswitches to modulate the CXCR3 chemokine receptor with light." Beilstein Journal of Organic Chemistry 15 (October 23, 2019): 2509–23. http://dx.doi.org/10.3762/bjoc.15.244.

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We report a detailed structure–activity relationship for the scaffold of VUF16216, a compound we have previously communicated as a small-molecule efficacy photoswitch for the peptidergic chemokine GPCR CXCR3. A series of photoswitchable azobenzene ligands was prepared through various synthetic strategies and multistep syntheses. Photochemical and pharmacological properties were used to guide the design iterations. Investigations of positional and substituent effects reveal that halogen substituents on the ortho-position of the outer ring are preferred for conferring partial agonism on the cis form of the ligands. This effect could be expanded by an electron-donating group on the para-position of the central ring. A variety of efficacy differences between the trans and cis forms emerges from these compounds. Tool compounds VUF15888 (4d) and VUF16620 (6e) represent more subtle efficacy switches, while VUF16216 (6f) displays the largest efficacy switch, from antagonism to full agonism. The compound class disclosed here can aid in new photopharmacology studies of CXCR3 signaling.

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25

Rachmawati, Dian, Mochammad Fahmi, Muhammad Abdjan, Eddy Wasito, Imam Siswanto, Nurzafirah Mazlan, Jazirotur Rohmah, and Afaf Baktir. "In Vitro Assessment on Designing Novel Antibiofilms of Pseudomonas aeruginosa Using a Computational Approach." Molecules 27, no. 24 (December 15, 2022): 8935. http://dx.doi.org/10.3390/molecules27248935.

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An anti-biofilm that can inhibit the matrix of biofilm formation is necessary to prevent recurrent and chronic Pseudomonas aeruginosa infection. This study aimed to design compounds with a new mechanism through competitive inhibitory activity against phosphomannomutase/phosphoglucomutase (PMM/PGM), using in vitro assessment and a computational (in silico) approach. The active site of PMM/PGM was assessed through molecular redocking using L-tartaric acid as the native ligand and other small molecules, such as glucaric acid, D-sorbitol, and ascorbic acid. The docking program set the small molecules to the active site, showing a stable complex formation. Analysis of structural similarity, bioavailability, absorption, distribution, metabolism, excretion, and toxicity properties proved the potential application of ligands as an anti-biofilm. In vitro assessment with crystal violet showed that the ligands could reach up to 95.87% inhibition at different concentrations. The nitrocellulose membrane and scanning electron microscopic visualization showed that the untreated P. aeruginosa biofilm was denser than the ligand-treated biofilm.

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26

Wu, Guanhui, Desiree Tillo, Sreejana Ray, Ta-Chau Chang, John S. Schneekloth, Charles Vinson, and Danzhou Yang. "Custom G4 Microarrays Reveal Selective G-Quadruplex Recognition of Small Molecule BMVC: A Large-Scale Assessment of Ligand Binding Selectivity." Molecules 25, no. 15 (July 30, 2020): 3465. http://dx.doi.org/10.3390/molecules25153465.

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G-quadruplexes (G4) are considered new drug targets for human diseases such as cancer. More than 10,000 G4s have been discovered in human chromatin, posing challenges for assessing the selectivity of a G4-interactive ligand. 3,6-bis(1-Methyl-4-vinylpyridinium) carbazole diiodide (BMVC) is the first fluorescent small molecule for G4 detection in vivo. Our previous structural study shows that BMVC binds to the MYC promoter G4 (MycG4) with high specificity. Here, we utilize high-throughput, large-scale custom DNA G4 microarrays to analyze the G4-binding selectivity of BMVC. BMVC preferentially binds to the parallel MycG4 and selectively recognizes flanking sequences of parallel G4s, especially the 3′-flanking thymine. Importantly, the microarray results are confirmed by orthogonal NMR and fluorescence binding analyses. Our study demonstrates the potential of custom G4 microarrays as a platform to broadly and unbiasedly assess the binding selectivity of G4-interactive ligands, and to help understand the properties that govern molecular recognition.

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27

Andelescu, Adelina A., Sorina Ilies (b. Motoc), Carmen Cretu, Evelyn Popa, Sorin Marinescu, Benoît Heinrich, Florica Manea, Sorina Negrea, Bertrand Donnio, and Elisabeta I. Szerb. "Pentacoordinated Liquid Crystalline Zn(II) Complex Organized in Smectic Mesophase: Synthesis, Structural and Electrochemical Properties." Applied Sciences 12, no. 16 (August 19, 2022): 8306. http://dx.doi.org/10.3390/app12168306.

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The synthesis and structural characterization of a new liquid crystalline coordination complex based on pentacoordinated Zn(II) metal centre with the coordination fulfilled by the tridentate chelating N^N^N 2,2′;6′,2″-terpyridine ligand and two monoanionic gallates decorated with several long alkyl chains is described. The mesomorphic properties were accurately investigated by small- and wide-angle X-ray scattering studies. Despite the bulky coordination around the metal centre, the complex self-organizes into a smectic phase and, based on the structural and geometrical parameters, a model for the supramolecular organization in the liquid crystalline phase is proposed. Electrochemical investigations showed the importance of the molecular structure of the coordination complex in enhancing its aqueous sensing capacities: the bulky organic ligands form an organic shell separating the metal centres and favouring the redox system through their reduction followed by stripping.

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28

Méndez-Álvarez, Domingo, Maria F. Torres-Rojas, Edgar E. Lara-Ramirez, Laurence A. Marchat та Gildardo Rivera. "Ligand-Based Virtual Screening, Molecular Docking, and Molecular Dynamic Simulations of New β-Estrogen Receptor Activators with Potential for Pharmacological Obesity Treatment". Molecules 28, № 11 (27 травня 2023): 4389. http://dx.doi.org/10.3390/molecules28114389.

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Obesity is a pandemic and a serious health problem in developed and undeveloped countries. Activation of estrogen receptor beta (ERβ) has been shown to promote weight loss without modifying caloric intake, making it an attractive target for developing new drugs against obesity. This work aimed to predict new small molecules as potential ERβ activators. A ligand-based virtual screening of the ZINC15, PubChem, and Molport databases by substructure and similarity was carried out using the three-dimensional organization of known ligands as a reference. A molecular docking screening of FDA-approved drugs was also conducted as a repositioning strategy. Finally, selected compounds were evaluated by molecular dynamic simulations. Compounds 1 (−24.27 ± 0.34 kcal/mol), 2 (−23.33 ± 0.3 kcal/mol), and 6 (−29.55 ± 0.51 kcal/mol) showed the best stability on the active site in complex with ERβ with an RMSD < 3.3 Å. RMSF analysis showed that these compounds do not affect the fluctuation of the Cα of ERβ nor the compactness according to the radius of gyration. Finally, an in silico evaluation of ADMET showed they are safe molecules. These results suggest that new ERβ ligands could be promising molecules for obesity control.

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29

Lenz, Tobias, Philipp Nicol, Maria Isabel Castellanos, Leif-Christopher Engel, Anna Lena Lahmann, Christoph Alexiou, and Michael Joner. "Small Dimension—Big Impact! Nanoparticle-Enhanced Non-Invasive and Intravascular Molecular Imaging of Atherosclerosis In Vivo." Molecules 25, no. 5 (February 25, 2020): 1029. http://dx.doi.org/10.3390/molecules25051029.

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Extensive translational research has provided considerable progress regarding the understanding of atherosclerosis pathophysiology over the last decades. In contrast, implementation of molecular in vivo imaging remains highly limited. In that context, nanoparticles represent a useful tool. Their variable shape and composition assure biocompatibility and stability within the environment of intended use, while the possibility of conjugating different ligands as well as contrast dyes enable targeting of moieties of interest on a molecular level and visualization throughout various imaging modalities. These characteristics have been exploited by a number of preclinical research approaches aimed at advancing understanding of vascular atherosclerotic disease, in order to improve identification of high-risk lesions prior to oftentimes fatal thromboembolic events. Furthermore, the combination of these targeted nanoparticles with therapeutic agents offers the potential of site-targeted drug delivery with minimized systemic secondary effects. This review gives an overview of different groups of targeted nanoparticles, designed for in vivo molecular imaging of atherosclerosis as well as an outlook on potential combined diagnostic and therapeutic applications.

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30

Hagler, Lauren D., Sarah E. Bonson, Philip A. Kocheril, and Steven C. Zimmerman. "Assessing the feasibility and stability of uracil base flipping in RNA–small molecule complexes using molecular dynamics simulations." Canadian Journal of Chemistry 98, no. 6 (June 2020): 261–69. http://dx.doi.org/10.1139/cjc-2019-0421.

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Small molecules can be used to target RNAs that mediate disease. A fundamental understanding of binding interactions between RNA and small molecules and the structure of their complexes will further inform the design of new targeting agents. Two small molecule ligands were investigated for their ability to recognize the expanded CUG repeat sequence in RNA, the causative agent of myotonic dystrophy type 1. We report the use of molecular dynamics simulations to explore small molecule–RNA complexes and the finding of a stabilized base flipped conformation at UU mismatches. The results of this computational study support experimental observations and suggest that base flipping is feasible for CUG-repeat RNA.

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31

Schmidt, Denis, Magdalena M. Scharf, Dominique Sydow, Eva Aßmann, Maria Martí-Solano, Marina Keul, Andrea Volkamer, and Peter Kolb. "Analyzing Kinase Similarity in Small Molecule and Protein Structural Space to Explore the Limits of Multi-Target Screening." Molecules 26, no. 3 (January 26, 2021): 629. http://dx.doi.org/10.3390/molecules26030629.

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While selective inhibition is one of the key assets for a small molecule drug, many diseases can only be tackled by simultaneous inhibition of several proteins. An example where achieving selectivity is especially challenging are ligands targeting human kinases. This difficulty arises from the high structural conservation of the kinase ATP binding sites, the area targeted by most inhibitors. We investigated the possibility to identify novel small molecule ligands with pre-defined binding profiles for a series of kinase targets and anti-targets by in silico docking. The candidate ligands originating from these calculations were assayed to determine their experimental binding profiles. Compared to previous studies, the acquired hit rates were low in this specific setup, which aimed at not only selecting multi-target kinase ligands, but also designing out binding to anti-targets. Specifically, only a single profiled substance could be verified as a sub-micromolar, dual-specific EGFR/ErbB2 ligand that indeed avoided its selected anti-target BRAF. We subsequently re-analyzed our target choice and in silico strategy based on these findings, with a particular emphasis on the hit rates that can be expected from a given target combination. To that end, we supplemented the structure-based docking calculations with bioinformatic considerations of binding pocket sequence and structure similarity as well as ligand-centric comparisons of kinases. Taken together, our results provide a multi-faceted picture of how pocket space can determine the success of docking in multi-target drug discovery efforts.

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32

Mendes, Eduarda, Israa M. Aljnadi, Bárbara Bahls, Bruno L. Victor, and Alexandra Paulo. "Major Achievements in the Design of Quadruplex-Interactive Small Molecules." Pharmaceuticals 15, no. 3 (February 28, 2022): 300. http://dx.doi.org/10.3390/ph15030300.

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Organic small molecules that can recognize and bind to G-quadruplex and i-Motif nucleic acids have great potential as selective drugs or as tools in drug target discovery programs, or even in the development of nanodevices for medical diagnosis. Hundreds of quadruplex-interactive small molecules have been reported, and the challenges in their design vary with the intended application. Herein, we survey the major achievements on the therapeutic potential of such quadruplex ligands, their mode of binding, effects upon interaction with quadruplexes, and consider the opportunities and challenges for their exploitation in drug discovery.

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33

Okochi, Hiroshi, and Peter Brimblecombe. "Potential Trace Metal–Organic Complexation in the Atmosphere." Scientific World JOURNAL 2 (2002): 767–86. http://dx.doi.org/10.1100/tsw.2002.132.

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It is possible that metal–organic complexation enhances the uptake of gaseous organic compounds and the solubility of metals in aerosols and atmospheric water. We investigated potential atmospheric organic ligands and the enhanced uptake of hydroxy-, oxo-, and dicarboxylic acids as well as dicarbonyls into atmospheric aqueous aerosol. We examined complexation with transition metals (iron, manganese, nickel, copper, zinc) and lead on the basis of available references and our experimental data. Humic-like substances are most likely ligands in the atmosphere, although this is a poorly characterized material. A number of polycarboxylic acids and hydroxy forms (e.g., citric and tartronic acids) effectively complex metals such as copper in atmospheric aerosols. The simple equilibrium model calculations show that the effect of the complexation on the gas–aqueous phase partition of gaseous atmospheric ligands is quite small for the ligands with the high physical Henry’s law constants, e.g., dicarboxylic acids represented by oxalic acid, even if they have high affinity with metal ions. The lower Henry’s law constants of the α-dicarbonyls, such as glyoxal and methylglyoxal, mean that the complexation could lead to profound increases in their partition into the aqueous phase. Despite quantum mechanical arguments for copper–glyoxal complexes, experiments showed no evidence of complexation between either hydrated or unhydrated α-dicarbonyls and the cupric ion. By contrast the β-dicarbonyl, malondialdehyde, has properties that would allow it to partition into atmospheric water via the complexation with metal ions under some conditions.

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34

Malikanti, Ramesh, Rajender Vadija, Hymavathi Veeravarapu, Kiran Kumar Mustyala, Vasavi Malkhed, and Uma Vuruputuri. "Identification of small molecular ligands as potent inhibitors of fatty acid metabolism in Mycobacterium tuberculosis." Journal of Molecular Structure 1150 (December 2017): 227–41. http://dx.doi.org/10.1016/j.molstruc.2017.08.090.

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35

Codina, Josep-Ramon, Marcello Mascini, Emre Dikici, Sapna K. Deo, and Sylvia Daunert. "Accelerating the Screening of Small Peptide Ligands by Combining Peptide-Protein Docking and Machine Learning." International Journal of Molecular Sciences 24, no. 15 (July 29, 2023): 12144. http://dx.doi.org/10.3390/ijms241512144.

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This research introduces a novel pipeline that couples machine learning (ML), and molecular docking for accelerating the process of small peptide ligand screening through the prediction of peptide-protein docking. Eight ML algorithms were analyzed for their potential. Notably, Light Gradient Boosting Machine (LightGBM), despite having comparable F1-score and accuracy to its counterparts, showcased superior computational efficiency. LightGBM was used to classify peptide-protein docking performance of the entire tetrapeptide library of 160,000 peptide ligands against four viral envelope proteins. The library was classified into two groups, ‘better performers’ and ‘worse performers’. By training the LightGBM algorithm on just 1% of the tetrapeptide library, we successfully classified the remaining 99%with an accuracy range of 0.81–0.85 and an F1-score between 0.58–0.67. Three different molecular docking software were used to prove that the process is not software dependent. With an adjustable probability threshold (from 0.5 to 0.95), the process could be accelerated by a factor of at least 10-fold and still get 90–95% concurrence with the method without ML. This study validates the efficiency of machine learning coupled to molecular docking in rapidly identifying top peptides without relying on high-performance computing power, making it an effective tool for screening potential bioactive compounds.

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36

Guzowska, Magdalena, Monika Kalinowska, and Wlodzimierz Lewandowski. "“Good Fashion is Evolution, Not Revolution” - Methods to Enhance Existing Anticancer Medicines, Primarily with the Use of Transition Metal." Anti-Cancer Agents in Medicinal Chemistry 18, no. 4 (July 17, 2018): 476–87. http://dx.doi.org/10.2174/1871520618666171129213132.

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The constant search for successful cancer therapies lasts for decades. Apart from the huge scientific effort and enormous sum of spent money, only a small amount of newly developed medicines move into clinical use (only 94 registered anticancer drugs in the last 12 years). Anticancer regimes are still overcome by drugs invented over 50 years ago such as cisplatin and doxorubicin. Significant progress in the development of improved anticancer drugs was made due to multiple studies on the relationship between the molecular structure of chemical compounds and their cytostatic activity. A number of ligands (mainly organic) with quite effective anticancer properties are known, but they show insufficient activity, selectivity and multidrug resistance. Formation of transition metal – ligand complexes (with proven anticancer effect) changes the properties of the latter. The factors that affect the cytotoxic properties of metal complexes are: the type of ligand and metal, the nature of the connection between metal and ligand, and the distribution of electronic charge density in the formed complexes. Here, we report the recent efforts to improve existing compounds with confirmed anticancer activity. They seem to be unappreciated as their effects appear to be less spectacular than that of targeted anticancer drugs (i.e. based on antibodies or small RNAs).

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37

Chen, Xiao-Ming. "Crystal Engineering and Applications of Functional Metal-Organic Frameworks." Acta Crystallographica Section A Foundations and Advances 70, a1 (August 5, 2014): C16. http://dx.doi.org/10.1107/s2053273314099835.

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As a new kind of molecular materials composed of metal ions (or clusters) and organic bridging ligands that are interconnected by coordination bonds, porous metal-organic frameworks (MOFs) have many useful characteristics, such as high crystallinity, high porosity, structural diversity, designable frameworks, framework flexibility, as well as unique and modifiable organic pore surface. Therefore, they exhibit very promising potential applications in molecular adsorption/separation, catalysis, and sensors, etc. For example, they can be used for selective adsorption and separation of different gas molecules, such as CO2 and N2, capture of CO2 [2], sensing of small organic molecules and gas molecules, such as O2 and CO2, as well as catalysts and devices for solid-phase microextraction. In this presentation, the design and synthesis, unique pore surface, interesting functionalities will be presented by selected examples, in particular those of metal-azolate frameworks (MAFs) and a few devices useful for practical applications, from our group [1-3]. This work was supported by MoST (973 project) and NSFC.

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38

Ye, Xiaoqing, Jean-François Gaucher, Michel Vidal, and Sylvain Broussy. "A Structural Overview of Vascular Endothelial Growth Factors Pharmacological Ligands: From Macromolecules to Designed Peptidomimetics." Molecules 26, no. 22 (November 9, 2021): 6759. http://dx.doi.org/10.3390/molecules26226759.

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The vascular endothelial growth factor (VEGF) family of cytokines plays a key role in vasculogenesis, angiogenesis, and lymphangiogenesis. VEGF-A is the main member of this family, alongside placental growth factor (PlGF), VEGF-B/C/D in mammals, and VEGF-E/F in other organisms. To study the activities of these growth factors under physiological and pathological conditions, resulting in therapeutic applications in cancer and age-related macular degeneration, blocking ligands have been developed. These have mostly been large biomolecules like antibodies. Ligands with high affinities, at least in the nanomolar range, and accurate structural data from X-ray crystallography and NMR spectroscopy have been described. They constitute the main focus of this overview, which evidences similarities and differences in their binding modes. For VEGF-A ligands, and to a limited extent also for PlGF, a transition is now observed towards developing smaller ligands like nanobodies and peptides. These include unnatural amino acids and chemical modifications for designed and improved properties, such as serum stability and greater affinity. However, this review also highlights the scarcity of such small molecular entities and the striking lack of small organic molecule ligands. It also shows the gap between the rather large array of ligands targeting VEGF-A and the general absence of ligands binding other VEGF members, besides some antibodies. Future developments in these directions are expected in the upcoming years, and the study of these growth factors and their promising therapeutic applications will be welcomed.

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39

Lipiński, Piotr, Piotr Kosson, Joanna Matalińska, Piotr Roszkowski, Zbigniew Czarnocki, Małgorzata Jarończyk, Aleksandra Misicka, Jan Dobrowolski, and Joanna Sadlej. "Fentanyl Family at the Mu-Opioid Receptor: Uniform Assessment of Binding and Computational Analysis." Molecules 24, no. 4 (February 19, 2019): 740. http://dx.doi.org/10.3390/molecules24040740.

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Interactions of 21 fentanyl derivatives with μ-opioid receptor (μOR) were studied using experimental and theoretical methods. Their binding to μOR was assessed with radioligand competitive binding assay. A uniform set of binding affinity data contains values for two novel and one previously uncharacterized derivative. The data confirms trends known so far and thanks to their uniformity, they facilitate further comparisons. In order to provide structural hypotheses explaining the experimental affinities, the complexes of the studied derivatives with μOR were modeled and subject to molecular dynamics simulations. Five common General Features (GFs) of fentanyls’ binding modes stemmed from these simulations. They include: GF1) the ionic interaction between D147 and the ligands’ piperidine NH+ moiety; GF2) the N-chain orientation towards the μOR interior; GF3) the other pole of ligands is directed towards the receptor outlet; GF4) the aromatic anilide ring penetrates the subpocket formed by TM3, TM4, ECL1 and ECL2; GF5) the 4-axial substituent (if present) is directed towards W318. Except for the ionic interaction with D147, the majority of fentanyl-μOR contacts is hydrophobic. Interestingly, it was possible to find nonlinear relationships between the binding affinity and the volume of the N-chain and/or anilide’s aromatic ring. This kind of relationships is consistent with the apolar character of interactions involved in ligand–receptor binding. The affinity reaches the optimum for medium size while it decreases for both large and small substituents. Additionally, a linear correlation between the volumes and the average dihedral angles of W293 and W133 was revealed by the molecular dynamics study. This seems particularly important, as the W293 residue is involved in the activation processes. Further, the Y326 (OH) and D147 (Cγ) distance found in the simulations also depends on the ligands’ size. In contrast, neither RMSF measures nor D114/Y336 hydrations show significant structure-based correlations. They also do not differentiate studied fentanyl derivatives. Eventually, none of 14 popular scoring functions yielded a significant correlation between the predicted and observed affinity data (R < 0.30, n = 28).

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40

GURBYCH, A. "METHOD SUPER LEARNING FOR DETERMINATION OF MOLECULAR RELATIONSHIP." Herald of Khmelnytskyi National University. Technical sciences 307, no. 2 (May 2, 2022): 14–24. http://dx.doi.org/10.31891/2307-5732-2022-307-2-14-24.

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This paper uses the Super Learning principle to predict the molecular affinity between the receptor (large biomolecule) and ligands (small organic molecules). Meta-models study the optimal combination of individual basic models in two consecutive ensembles – classification and regression. Each costume contains six models of machine learning, which are combined by stacking. Base models include the reference vector method, random forest, gradient boosting, neural graph networks, direct propagation, and transformers. The first ensemble predicts binding probability and classifies all candidate molecules to the selected receptor into active and inactive. Ligands recognized as involved by the first ensemble are fed to the second ensemble, which assumes the degree of their affinity for the receptor in the form of an inhibition factor (Ki). A feature of the method is the rejection of the use of atomic coordinates of individual molecules and their complexes – thus eliminating experimental errors in sample preparation and measurement of nuclear coordinates and the method to determine the affinity of biomolecules with unknown spatial configurations. It is shown that meta-learning increases the response (Recall) of the classification ensemble by 34.9% and the coefficient of determination (R2) of the regression ensemble by 21% compared to the average values. This paper shows that an ensemble with meta-stacking is an asymptotically optimal system for learning. The feature of Super Learning is to use k-fold cross-validation to form first-level predictions that teach second-level models — or meta-models — that combine first-level models optimally. The ability to predict the molecular affinity of six machine learning models is studied, and the efficiency improvement is due to the combination of models in the ensemble by the stacking method. Models that are combined into two consecutive ensembles are shown.

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41

Luh, George Y., and Moon K. Song. "Characterization of the low mol. wt zinc-binding ligand from rat small intestine by comparison to the organic zinc-binding ligands." Comparative Biochemistry and Physiology Part B: Comparative Biochemistry 91, no. 3 (January 1988): 569–76. http://dx.doi.org/10.1016/0305-0491(88)90023-5.

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42

Porter, John, Andrew Payne, Ian Whitcombe, Ben de Candole, Daniel Ford, Rachel Garlish, Adam Hold, et al. "Atropisomeric small molecule Bcl-2 ligands: Determination of bioactive conformation." Bioorganic & Medicinal Chemistry Letters 19, no. 6 (March 2009): 1767–72. http://dx.doi.org/10.1016/j.bmcl.2009.01.071.

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43

Ogura, Yusaku, Masahiro Nakano, Hajime Maeda, Masahito Segi, and Taniyuki Furuyama. "Cationic Axial Ligand Effects on Sulfur-Substituted Subphthalocyanines." Molecules 27, no. 9 (April 26, 2022): 2766. http://dx.doi.org/10.3390/molecules27092766.

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Herein, we report the synthesis of sulfur-substituted boron(III) subphthalocyanines (SubPcs) with cationic axial ligands. Subphthalocyanines were synthesized by a condensation reaction using the corresponding phthalonitriles and boron trichloride as a template. An aminoalkyl group was introduced on the central boron atom; this process was followed by N-methylation to introduce a cationic axial ligand. The peripheral sulfur groups shifted the Q band of SubPcs to a longer wavelength. The cationic axial ligands increased the polarity and enhanced the hydrophilicity of SubPcs. The effect of axial ligands on absorption and fluorescence properties is generally small. However, a further red shift was observed by introducing cationic axial ligands into the sulfur-substituted SubPcs. This change is similar to that in sulfur-substituted silicon(IV) phthalocyanines. The unique effect of the cationic axial ligand was extensively investigated by theoretical calculations and electrochemistry. In particular, the precise oxidation potential was determined using ionization potential measurements. Thus, the results of the present study provide a novel strategy for developing functional dyes and pigments based on SubPcs.

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44

Wang, Yuanqiang, Haiqiong Guo, Zhiwei Feng, Siyi Wang, Yuxuan Wang, Qingxiu He, Guangping Li, Weiwei Lin, Xiang-Qun Xie, and Zhihua Lin. "PD-1-Targeted Discovery of Peptide Inhibitors by Virtual Screening, Molecular Dynamics Simulation, and Surface Plasmon Resonance." Molecules 24, no. 20 (October 21, 2019): 3784. http://dx.doi.org/10.3390/molecules24203784.

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The blockade of the programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) pathway plays a critical role in cancer immunotherapy by reducing the immune escape. Five monoclonal antibodies that antagonized PD-1/PD-L1 interaction have been approved by the Food and Drug Administration (FDA) and marketed as immunotherapy for cancer treatment. However, some weaknesses of antibodies, such as high cost, low stability, poor amenability for oral administration, and immunogenicity, should not be overlooked. To overcome these disadvantages, small-molecule inhibitors targeting PD-L1 were developed. In the present work, we applied in silico and in vitro approaches to develop short peptides targeting PD-1 as chemical probes for the inhibition of PD-1–PD-L1 interaction. We first predicted the potential binding pocket on PD-1/PD-L1 protein–protein interface (PPI). Sequentially, we carried out virtual screening against our in-house peptide library to identify potential ligands. WANG-003, WANG-004, and WANG-005, three of our in-house peptides, were predicted to bind to PD-1 with promising docking scores. Next, we conducted molecular docking and molecular dynamics (MD) simulation for the further analysis of interactions between our peptides and PD-1. Finally, we evaluated the affinity between peptides and PD-1 by surface plasmon resonance (SPR) binding technology. The present study provides a new perspective for the development of PD-1 inhibitors that disrupt PD-1–PD-L1 interactions. These promising peptides have the potential to be utilized as a novel chemical probe for further studies, as well as providing a foundation for further designs of potent small-molecule inhibitors targeting PD-1.

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45

Farag, Marc, Charline Kieffer, Nicolas Guedeney, Anne Sophie Voisin-Chiret, and Jana Sopkova-de Oliveira Santos. "Computational Tool to Design Small Synthetic Inhibitors Selective for XIAP-BIR3 Domain." Molecules 28, no. 13 (June 30, 2023): 5155. http://dx.doi.org/10.3390/molecules28135155.

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X-linked inhibitor of apoptosis protein (XIAP) exercises its biological function by locking up and inhibiting essential caspase-3, -7 and -9 toward apoptosis execution. It is overexpressed in multiple human cancers, and it plays an important role in cancer cells’ death skipping. Inhibition of XIAP-BIR3 domain and caspase-9 interaction was raised as a promising strategy to restore apoptosis in malignancy treatment. However, XIAP-BIR3 antagonists also inhibit cIAP1-2 BIR3 domains, leading to serious side effects. In this study, we worked on a theoretical model that allowed us to design and optimize selective synthetic XIAP-BIR3 antagonists. Firstly, we assessed various MM-PBSA strategies to predict the XIAP-BIR3 binding affinities of synthetic ligands. Molecular dynamics simulations using hydrogen mass repartition as an additional parametrization with and without entropic term computed by the interaction entropy approach produced the best correlations. These simulations were then exploited to generate 3D pharmacophores. Following an optimization with a training dataset, five features were enough to model XIAP-BIR3 synthetic ligands binding to two hydrogen bond donors, one hydrogen bond acceptor and two hydrophobic groups. The correlation between pharmacophoric features and computed MM-PBSA free energy revealed nine residues as crucial for synthetic ligand binding: Thr308, Glu314, Trp323, Leu307, Asp309, Trp310, Gly306, Gln319 and Lys297. Ultimately, and three of them seemed interesting to use to improve XIAP-BR3 versus cIAP-BIR3 selectivity: Lys297, Thr308 and Asp309.

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46

Defelipe, Lucas, Juan Arcon, Carlos Modenutti, Marcelo Marti, Adrián Turjanski, and Xavier Barril. "Solvents to Fragments to Drugs: MD Applications in Drug Design." Molecules 23, no. 12 (December 11, 2018): 3269. http://dx.doi.org/10.3390/molecules23123269.

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Simulations of molecular dynamics (MD) are playing an increasingly important role in structure-based drug discovery (SBDD). Here we review the use of MD for proteins in aqueous solvation, organic/aqueous mixed solvents (MDmix) and with small ligands, to the classic SBDD problems: Binding mode and binding free energy predictions. The simulation of proteins in their condensed state reveals solvent structures and preferential interaction sites (hot spots) on the protein surface. The information provided by water and its cosolvents can be used very effectively to understand protein ligand recognition and to improve the predictive capability of well-established methods such as molecular docking. The application of MD simulations to the study of the association of proteins with drug-like compounds is currently only possible for specific cases, as it remains computationally very expensive and labor intensive. MDmix simulations on the other hand, can be used systematically to address some of the common tasks in SBDD. With the advent of new tools and faster computers we expect to see an increase in the application of mixed solvent MD simulations to a plethora of protein targets to identify new drug candidates.

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47

Karasev, Dmitry A., Boris N. Sobolev, Alexey A. Lagunin, Dmitry A. Filimonov, and Vladimir V. Poroikov. "The method predicting interaction between protein targets and small-molecular ligands with the wide applicability domain." Computational Biology and Chemistry 98 (June 2022): 107674. http://dx.doi.org/10.1016/j.compbiolchem.2022.107674.

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48

Cho, Haeryung, Woo-Chang Son, Young-Shin Lee, Eun Jung Youn, Chi-Dug Kang, You-Soo Park, and Jaeho Bae. "Differential Effects of Histone Deacetylases on the Expression of NKG2D Ligands and NK Cell-Mediated Anticancer Immunity in Lung Cancer Cells." Molecules 26, no. 13 (June 28, 2021): 3952. http://dx.doi.org/10.3390/molecules26133952.

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Histone acetylation is an epigenetic mechanism that regulates the expression of various genes, such as natural killer group 2, member D (NKG2D) ligands. These NKG2D ligands are the key molecules that activate immune cells expressing the NKG2D receptor. It has been observed that cancer cells overexpress histone deacetylases (HDACs) and show reduced acetylation of nuclear histones. Furthermore, HDAC inhibitors are known to upregulate the expression of NKG2D ligands. Humans have 18 known HDAC enzymes that are divided into four classes. At present, it is not clear which types of HDAC are involved in the expression of NKG2D ligands. We hypothesized that specific types of HDAC genes might be responsible for altering the expression of NKG2D ligands. In this study, we monitored the expression of NKG2D ligands and major histocompatibility complex (MHC) class I molecules in lung cancer cells which were treated with six selective HDAC inhibitors and specific small interfering RNAs (siRNAs). We observed that treatment with FK228, which is a selective HDAC1/2 inhibitor, also known as Romidepsin, induced NKG2D ligand expression at the transcriptional and proteomic levels in two different lung cancer cell lines. It also caused an increase in the susceptibility of NCI-H23 cells to NK cells. Silencing HDAC1 or HDAC2 using specific siRNAs increased NKG2D ligand expression. In conclusion, it appears that HDAC1 and HDAC2 might be the key molecules regulating the expression of NKG2D ligands. These results imply that specifically inhibiting HDAC1 and HDAC2 could induce the expression of NKG2D ligands and improve the NK cell-mediated anti-cancer immunity.

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Kovács, Attila, Christos Apostolidis, and Olaf Walter. "Competing Metal–Ligand Interactions in Tris(cyclopentadienyl)-cyclohexylisonitrile Complexes of Trivalent Actinides and Lanthanides." Molecules 27, no. 12 (June 14, 2022): 3811. http://dx.doi.org/10.3390/molecules27123811.

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The structure and bonding properties of 16 complexes formed by trivalent f elements (M=U, Np, Pu and lanthanides except for Pm and Pr) with cyclopentadienyl (Cp) and cyclohexylisonitrile (C≡NCy) ligands, (Cp)3M(C≡NCy), were studied by a joint experimental (XRD, NMR) and theoretical (DFT) analysis. For the large La(III) ion, the bis-adduct (Cp)3La(C≡NCy)2 could also be synthesized and characterized. The metal–ligand interactions, focusing on the comparison of the actinides and lanthanides as well as on the competition of the two different ligands for M, were elucidated using the Quantum Theory of Atoms in Molecules (QTAIM) and Natural Bond Orbital (NBO) models. The results point to interactions of comparable strengths with the anionic Cp and neutral C≡NCy ligands in the complexes. The structural and bonding properties of the actinide complexes reflect small but characteristic differences with respect to the lanthanide analogues. They include larger ligand-to-metal charge transfers as well as metal–ligand electron-sharing interactions. The most significant experimental marker of these covalent interactions is the C≡N stretching frequency.

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50

Li, Chaoqun, Xiaojia Zhao, Xiaomin Zhu, Pengtao Xie, and Guangju Chen. "Structural Studies of the 3′,3′-cGAMP Riboswitch Induced by Cognate and Noncognate Ligands Using Molecular Dynamics Simulation." International Journal of Molecular Sciences 19, no. 11 (November 9, 2018): 3527. http://dx.doi.org/10.3390/ijms19113527.

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Riboswtich RNAs can control gene expression through the structural change induced by the corresponding small-molecule ligands. Molecular dynamics simulations and free energy calculations on the aptamer domain of the 3′,3′-cGAMP riboswitch in the ligand-free, cognate-bound and noncognate-bound states were performed to investigate the structural features of the 3′,3′-cGAMP riboswitch induced by the 3′,3′-cGAMP ligand and the specificity of ligand recognition. The results revealed that the aptamer of the 3′,3′-cGAMP riboswitch in the ligand-free state has a smaller binding pocket and a relatively compact structure versus that in the 3′,3′-cGAMP-bound state. The binding of the 3′,3′-cGAMP molecule to the 3′,3′-cGAMP riboswitch induces the rotation of P1 helix through the allosteric communication from the binding sites pocket containing the J1/2, J1/3 and J2/3 junction to the P1 helix. Simultaneously, these simulations also revealed that the preferential binding of the 3′,3′-cGAMP riboswitch to its cognate ligand, 3′,3′-cGAMP, over its noncognate ligand, c-di-GMP and c-di-AMP. The J1/2 junction in the 3′,3′-cGAMP riboswitch contributing to the specificity of ligand recognition have also been found.

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