Journal articles: 'Nanomagnetism - Small Molecular Organic Ligands'

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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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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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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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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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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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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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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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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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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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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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Polowin, Joel, Robert Poe, and 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, no. 7 (July 1, 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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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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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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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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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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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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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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Benz, Armin, Vijay Singh, Thomas U. Mayer, and Jörg S. Hartig. "Identification of Novel Quadruplex Ligands from Small Molecule Libraries by FRET-Based High-Throughput Screening." ChemBioChem 12, no. 9 (May 26, 2011): 1422–26. http://dx.doi.org/10.1002/cbic.201100094.

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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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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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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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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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Trzęsowska, Natasza, Rafał Wysokiński, Mariusz Michalczyk, Wiktor Zierkiewicz, and Steve Scheiner. "Trapping of Small Molecules within Single or Double Cyclo[18]carbon Rings." Molecules 28, no. 5 (February 25, 2023): 2157. http://dx.doi.org/10.3390/molecules28052157.

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The encapsulation of a set of small molecules, H2, CO, CO2, SO2, and SO3, by a circular C18 ring is investigated by quantum calculations. These ligands lie near the center of the ring but, with the exception of H2, are disposed roughly perpendicular to the ring plane. Their binding energies with the C18 vary from 1.5 kcal/mol for H2 up to 5.7 kcal/mol for SO2, and the bonding is dominated by dispersive interactions spread over the entire ring. The binding of these ligands on the outside of the ring is weaker but allows the opportunity for each to bond covalently with the ring. A pair of C18 units lie parallel to one another. This pair can bind each of these ligands in the area between them with only small perturbations of the double ring geometry. The binding energies of these ligands to this double ring configuration are amplified by some 50% compared to the single ring systems. The presented data concerning the trapping of small molecules may have larger implications regarding hydrogen storage or air pollution reduction.

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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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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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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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Barozzi, Annalisa, R. Ashton Lavoie, Kevin N. Day, Raphael Prodromou, and Stefano Menegatti. "Affibody-Binding Ligands." International Journal of Molecular Sciences 21, no. 11 (May 27, 2020): 3769. http://dx.doi.org/10.3390/ijms21113769.

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While antibodies remain established therapeutic and diagnostic tools, other protein scaffolds are emerging as effective and safer alternatives. Affibodies in particular are a new class of small proteins marketed as bio-analytic reagents. They feature tailorable binding affinity, low immunogenicity, high tissue permeation, and high expression titer in bacterial hosts. This work presents the development of affibody-binding peptides to be utilized as ligands for their purification from bacterial lysates. Affibody-binding candidates were identified by screening a peptide library simultaneously against two model affibodies (anti-immunoglobulin G (IgG) and anti-albumin) with the aim of selecting peptides targeting the conserved domain of affibodies. An ensemble of homologous sequences identified from screening was synthesized on Toyopearl® resin and evaluated via binding studies to select sequences that afford high product binding and recovery. The affibody–peptide interaction was also evaluated by in silico docking, which corroborated the targeting of the conserved domain. Ligand IGKQRI was validated through purification of an anti-ErbB2 affibody from an Escherichia coli lysate. The values of binding capacity (~5 mg affibody per mL of resin), affinity (KD ~1 μM), recovery and purity (64–71% and 86–91%), and resin lifetime (100 cycles) demonstrate that IGKQRI can be employed as ligand in affibody purification processes.

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Qian, Mingcheng, Zhengyang Sun, Xin Chen, and Serge Van Calenbergh. "Study of G protein-coupled receptors dimerization: From bivalent ligands to drug-like small molecules." Bioorganic Chemistry 140 (November 2023): 106809. http://dx.doi.org/10.1016/j.bioorg.2023.106809.

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Jamshidiha, Mostafa, Thomas Lanyon-Hogg, Charlotte L. Sutherell, Gregory B. Craven, Montse Tersa, Elena De Vita, Delia Brustur, et al. "Identification of the first structurally validated covalent ligands of the small GTPase RAB27A." RSC Medicinal Chemistry 13, no. 2 (2022): 150–55. http://dx.doi.org/10.1039/d1md00225b.

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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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Pyrkov, Timothy V., Irina A. Sevostyanova, Elena V. Schmalhausen, Andrei N. Shkoporov, Andrei A. Vinnik, Vladimir I. Muronetz, Fedor F. Severin, and Peter O. Fedichev. "Structure-Based Design of Small-Molecule Ligands of Phosphofructokinase-2 Activating or Inhibiting Glycolysis." ChemMedChem 8, no. 8 (June 28, 2013): 1322–29. http://dx.doi.org/10.1002/cmdc.201300154.

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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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Iraji, Aida, Mahsima Khoshneviszadeh, Omidreza Firuzi, Mehdi Khoshneviszadeh, and Najmeh Edraki. "Novel small molecule therapeutic agents for Alzheimer disease: Focusing on BACE1 and multi-target directed ligands." Bioorganic Chemistry 97 (April 2020): 103649. http://dx.doi.org/10.1016/j.bioorg.2020.103649.

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Hawxwell, Samuel M., Harry Adams, and Lee Brammer. "Two-dimensional metal-organic frameworks containing linear dicarboxylates." Acta Crystallographica Section B Structural Science 62, no. 5 (September 18, 2006): 808–14. http://dx.doi.org/10.1107/s0108768106033283.

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The solvothermal synthesis of four two-dimensional metal-organic frameworks containing linear dicarboxylic acids as ligands for ZnII centres is described. Zn(BDC)(DMF) [(1) where BDC = benzene-1,4-dicarboxylic acid; DMF = N,N-dimethylformamide] adopts a common paddlewheel motif leading to a 44 grid network, whereas Zn3(BDC)3(EtOH)2 (2), Zn3(BDC)3(H2O)2·4DMF (3) and Zn3(BPDC)3(DMF)2·4DMF (4) each form networks with the relatively uncommon 36 topology based upon Zn3(O2CR)6 secondary building units. All contain coordinated solvent molecules, namely DMF [(1) and (4)], ethanol (2) or H2O (3). Comparison of structures (2) and (3) illustrates a clay-like flexibility in interplanar spacing which sheds light on the ability of the Zn3(BDC)3 framework to undergo desolvation and uptake of small solvent and gas molecules.

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35

Sun, Nannan, Congmin Yuan, Xiaojun Ma, Yonghui Wang, Xianfeng Gu, and Wei Fu. "Molecular Mechanism of Action of RORγt Agonists and Inverse Agonists: Insights from Molecular Dynamics Simulation." Molecules 23, no. 12 (December 3, 2018): 3181. http://dx.doi.org/10.3390/molecules23123181.

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As an attractive drug-target, retinoic acid receptor-related orphan receptor-gamma-t (RORγt) has been employed widely to develop clinically relevant small molecular modulators as potent therapy for autoimmune disease and cancer, but its molecular mechanism of action (MOA) remains unclear. In the present study, we designed and discovered two novel RORγt ligands that are similar in structure, but different in efficacy. Using fluorescence resonance energy transfer (FRET) assay, compound 1 was identified as an agonist with an EC50 of 3.7 μM (max. act.: 78%), while compound 2 as an inverse agonist with an IC50 value of 2.0 μM (max. inh.: 61%). We performed molecular dynamics (MD) simulations, and elucidated the MOA of RORγt agonist and inverse agonist. Through the analyses of our MD results, we found that, after RORγt is bound with the agonist 1, the side chain of Trp317 stays in the gauche- conformation, and thus helps to form the hydrogen bond, His479-Trp502, and a large hydrophobic network among H11, H11′, and H12. All these interactions stabilize the H12, and helps the receptor recruit the coactivator. When the RORγt is bound with the inverse agonist 2, the side chain of Trp317 is forced to adopt the trans conformation, and these presumed interactions are partially destroyed. Taken together, the critical role of residue Trp317 could be viewed as the driving force for the activation of RORγt.

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Bayer, Peter, Anja Matena, and Christine Beuck. "NMR Spectroscopy of supramolecular chemistry on protein surfaces." Beilstein Journal of Organic Chemistry 16 (October 9, 2020): 2505–22. http://dx.doi.org/10.3762/bjoc.16.203.

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As one of the few analytical methods that offer atomic resolution, NMR spectroscopy is a valuable tool to study the interaction of proteins with their interaction partners, both biomolecules and synthetic ligands. In recent years, the focus in chemistry has kept expanding from targeting small binding pockets in proteins to recognizing patches on protein surfaces, mostly via supramolecular chemistry, with the goal to modulate protein–protein interactions. Here we present NMR methods that have been applied to characterize these molecular interactions and discuss the challenges of this endeavor.

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37

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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Coban, Tomris, Cameron Robertson, Sianne Schwikkard, Richard Singer, and Adam LeGresley. "Synthesis and evaluation of bis(imino)anthracene derivatives as G-quadruplex ligands." RSC Medicinal Chemistry 12, no. 5 (2021): 751–57. http://dx.doi.org/10.1039/d0md00428f.

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The synthesis of a small number of bis(imino)anthracene derivatives is reported. They were evaluated via NMR for binding efficacy to the G-quadruplex-forming oligonucleotide sequence (TTGGGTT) and show activity against the HeLa cancer cell line.

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39

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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Figueiredo, Joana, Tiago Santos, André Miranda, Daniela Alexandre, Bernardo Teixeira, Pedro Simões, Jéssica Lopes-Nunes, and Carla Cruz. "Ligands as Stabilizers of G-Quadruplexes in Non-Coding RNAs." Molecules 26, no. 20 (October 13, 2021): 6164. http://dx.doi.org/10.3390/molecules26206164.

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The non-coding RNAs (ncRNA) are RNA transcripts with different sizes, structures and biological functions that do not encode functional proteins. RNA G-quadruplexes (rG4s) have been found in small and long ncRNAs. The existence of an equilibrium between rG4 and stem−loop structures in ncRNAs and its effect on biological processes remains unexplored. For example, deviation from the stem−loop leads to deregulated mature miRNA levels, demonstrating that miRNA biogenesis can be modulated by ions or small molecules. In light of this, we report several examples of rG4s in certain types of ncRNAs, and the implications of G4 stabilization using small molecules, also known as G4 ligands, in the regulation of gene expression, miRNA biogenesis, and miRNA−mRNA interactions. Until now, different G4 ligands scaffolds were synthesized for these targets. The regulatory role of the above-mentioned rG4s in ncRNAs can be used as novel therapeutic approaches for adjusting miRNA levels.

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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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Kazmierski, Wieslaw, Neil Bifulco, Hanbiao Yang, Larry Boone, Felix DeAnda, Chris Watson, and Terry Kenakin. "Recent progress in discovery of small-molecule CCR5 chemokine receptor ligands as HIV-1 inhibitors." Bioorganic & Medicinal Chemistry 11, no. 13 (July 2003): 2663–76. http://dx.doi.org/10.1016/s0968-0896(03)00161-5.

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43

Derks, R. J. E., T. Letzel, C. F. Jong, A. Marle, H. Lingeman, R. Leurs, and H. Irth. "SEC–MS as an Approach to Isolate and Directly Identifying Small Molecular GPCR–Ligands from Complex Mixtures Without Labeling." Chromatographia 64, no. 7-8 (September 12, 2006): 379–85. http://dx.doi.org/10.1365/s10337-006-0058-9.

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44

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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45

Chang, Zhihua, Ya Ying Zheng, Johnsi Mathivanan, Vibhav A. Valsangkar, Jinxi Du, Reham A. I. Abou-Elkhair, Abdalla E. A. Hassan, and Jia Sheng. "Fluorescence-Based Binding Characterization of Small Molecule Ligands Targeting CUG RNA Repeats." International Journal of Molecular Sciences 23, no. 6 (March 19, 2022): 3321. http://dx.doi.org/10.3390/ijms23063321.

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Pathogenic CUG and CCUG RNA repeats have been associated with myotonic dystrophy type 1 and 2 (DM1 and DM2), respectively. Identifying small molecules that can bind these RNA repeats is of great significance to develop potential therapeutics to treat these neurodegenerative diseases. Some studies have shown that aminoglycosides and their derivatives could work as potential lead compounds targeting these RNA repeats. In this work, sisomicin, previously known to bind HIV-1 TAR, is investigated as a possible ligand for CUG RNA repeats. We designed a novel fluorescence-labeled RNA sequence of r(CUG)10 to mimic cellular RNA repeats and improve the detecting sensitivity. The interaction of sisomicin with CUG RNA repeats is characterized by the change of fluorescent signal, which is initially minimized by covalently incorporating the fluorescein into the RNA bases and later increased upon ligand binding. The results show that sisomicin can bind and stabilize the folded RNA structure. We demonstrate that this new fluorescence-based binding characterization assay is consistent with the classic UV Tm technique, indicating its feasibility for high-throughput screening of ligand-RNA binding interactions and wide applications to measure the thermodynamic parameters in addition to binding constants and kinetics when probing such interactions.

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Fairhead, Michael, Di Shen, Louis K. M. Chan, Ed D. Lowe, Timothy J. Donohoe, and Mark Howarth. "Love–Hate ligands for high resolution analysis of strain in ultra-stable protein/small molecule interaction." Bioorganic & Medicinal Chemistry 22, no. 19 (October 2014): 5476–86. http://dx.doi.org/10.1016/j.bmc.2014.07.029.

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47

Berdnikova, Daria V., Paolo Carloni, Sybille Krauß, and Giulia Rossetti. "Role and Perspective of Molecular Simulation-Based Investigation of RNA–Ligand Interaction: From Small Molecules and Peptides to Photoswitchable RNA Binding." Molecules 26, no. 11 (June 3, 2021): 3384. http://dx.doi.org/10.3390/molecules26113384.

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Aberrant RNA–protein complexes are formed in a variety of diseases. Identifying the ligands that interfere with their formation is a valuable therapeutic strategy. Molecular simulation, validated against experimental data, has recently emerged as a powerful tool to predict both the pose and energetics of such ligands. Thus, the use of molecular simulation may provide insight into aberrant molecular interactions in diseases and, from a drug design perspective, may allow for the employment of less wet lab resources than traditional in vitro compound screening approaches. With regard to basic research questions, molecular simulation can support the understanding of the exact molecular interaction and binding mode. Here, we focus on examples targeting RNA–protein complexes in neurodegenerative diseases and viral infections. These examples illustrate that the strategy is rather general and could be applied to different pharmacologically relevant approaches. We close this study by outlining one of these approaches, namely the light-controllable association of small molecules with RNA, as an emerging approach in RNA-targeting therapy.

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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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Symons, Martyn CR, and Raymond E. March. "Possible structures for H-Cu-CH3 molecules." Canadian Journal of Chemistry 79, no. 2 (February 1, 2001): 124–26. http://dx.doi.org/10.1139/v01-004.

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EPR spectra for H-Cu-CH3 molecules in glasses at 77 K show 63Cu hyperfine splitting that accords with a d1x2 y2 orbital for the semi-occupied molecular orbital (SOMO) rather than a d1z2 SOMO. The g-values also strongly imply a d1x2 y2 configuration. The estimated spin densities on the H- and -CH3 ligands are small. It is argued that the molecule must be strongly bent in order to favour this SOMO and that this bending may be induced by weak solvation.Key words : H-Cu-CH3, EPR spectra, molecular structure, hyperfine splitting.

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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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Journal articles on the topic 'Nanomagnetism - Small Molecular Organic Ligands'

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