Zeitschriftenartikel: „Pteridine ligands“

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Kaim, Wolfgang, Brigitte Schwederski, Oliver Heilmann und Fridmann M. Hornung. „Coordination compounds of pteridine, alloxazine and flavin ligands: structures and properties“. Coordination Chemistry Reviews 182, Nr. 1 (Februar 1999): 323–42. http://dx.doi.org/10.1016/s0010-8545(98)00193-3.

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Kaim, Wolfgang, Brigitte Schwederski, Oliver Heilmann und Fridmann M. Hornung. „ChemInform Abstract: Coordination Compounds of Pteridine, Alloxazine and Flavin Ligands: Structures and Properties.“ ChemInform 30, Nr. 18 (16.06.2010): no. http://dx.doi.org/10.1002/chin.199918312.

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Mullice, Lucy A., Huw J. Mottram, Andrew J. Hallett und Simon J. A. Pope. „Gold(I) Complexes Incorporating Emissive Mercapto-Pteridine Ligands: Syntheses, X-ray Structure, Luminescence and Preliminary Cytotoxic Evaluation“. European Journal of Inorganic Chemistry 2012, Nr. 18 (03.05.2012): 3054–60. http://dx.doi.org/10.1002/ejic.201200147.

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4

Sokolova, K. V., V. V. Stavytskyi, O. Yu Voskoboinik, O. A. Podpletnya und S. I. Kovalenko. „In silico and in vivo screening of triamterene synthetic analogues as promising diuretics“. Medicni perspektivi 27, Nr. 3 (30.09.2022): 4–15. http://dx.doi.org/10.26641/2307-0404.2022.3.265739.

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The modification of lead-compound aimed to the increasing of activity, decrement of toxicity or improvement of selectivity is one of the most important methods used for elaboration of novel medications. Natural compounds, approved or investigational drugs or just compounds with proved biological activity could be the lead-compound. Often the chemical modification of lead compounds is directed at the enhancement of ligand-biological target interactions. Abovementioned approach, namely structural modification of known drug triamterene was used for purposeful search for novel diuretics. The preliminary prognostication of ligand-target interactions and affinity levels allow to reduce quantity of experimental animals, synthesis, and pharmacological studies costs. Conducted studies revealed the series of promising 6,7-disubstituted pteridine-2,4(1H,3H)-diones with diuretic activity that comparable with pharmacological effect of triamterene. Aim – purposeful search for promising diuretics among structural analogues of triamterene that includes preliminary in silico studies, synthesis and in vivo screening of novel compounds for diuretic activity. Methods used: organic synthesis, physicochemical methods of analysis of organic compounds (NMR 1H-spectroscopy, chromato-mass spectrometry, elemental analysis). Prediction of affinity for a biological target, prediction of toxicity and lipophilicity of the combinatorial library, which was created on the basis of the drug triamterene, was carried out using computer services. Studies of compounds that affect the excretory function of the kidneys of rats were performed according to the generally accepted method of E.B. Berkhin with water load. Research of the probable mechanism was conducted by flexible molecular docking, as an approach of finding molecules with affinity to a specific biological target. Macromolecular data were downloaded from the Protein Data Bank (PDB) namely, the crystal structures of epithelial sodium channel (ENaC) ((PDB ID – 6WTH). The substantiation of potential diuretics design was conducted by in silico methods (prediction of affinity, ligand-enzyme interactions and pharmacokinetic characteristics). The structural modification of triamterene molecule was carried out by replacing of amino-group in positions 2, 4 and 7 by others “pharmacophore” fragments. Abovementioned transformation is aimed at the changing of ligand-enzyme interactions in active site, lipophility and toxicity. Synthesis of 6,7-disubstituted pteridine-2,4(1H,3H)-diones was conducted by condensation 5,6-diamino-2-oxo-(thioxo-)-2,3-dihydropyrimidin-4(1H)-ones with carbonyl-containing compounds or oxocarboxylic acids. The further modification of obtained compounds was performed by alkylation, hydrazinolysis and nucleophilic addition/elimination. The structure of obtained compounds was proven by elemental analysis, chromato-mass and 1H NMR-spectral analysis. The studies of synthesized compounds effect on excretion function of kidneys allowed to detect series of promising structural analogues of triamterene that exceed it in pharmacological activity by 27.3-99.0%. The “structure-biological activity” relationship was discussed and perspective of the further search of diuretics among abovementioned compounds were shown. The design of new biologically active compounds with diuretic activity was performed using in silico methodologies and realized by structural modification of the well-known diuretic triamterene. Traditional organic synthesis was used for preparation of target compounds, in vivo experiments were used to detect compounds with significant biological activity. Several effective compounds were identified among pteridines, which exceed the reference drug triamterene in terms of daily diuresis. The obtained results substantiate further purposeful search, in-depth research on experimental pathologies and study of the mechanism of action of potential diuretics among this class of compounds.

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Shamshad, Hina, Abdul Hafiz, Ismail I. Althagafi, Maria Saeed und Agha Zeeshan Mirza. „Characterization of the Trypanosoma brucei Pteridine Reductase Active- Site using Computational Docking and Virtual Screening Techniques“. Current Computer-Aided Drug Design 16, Nr. 5 (09.11.2020): 583–98. http://dx.doi.org/10.2174/1573409915666190827163327.

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Background: Human African trypanosomiasis is a fatal disease prevalent in approximately 36 sub-Saharan countries. Emerging reports of drug resistance in Trypanosoma brucei are a serious cause of concern as only limited drugs are available for the treatment of the disease. Pteridine reductase is an enzyme of Trypanosoma brucei. Methods: It plays a critical role in the pterin metabolic pathway that is absolutely essential for its survival in the human host. The success of finding a potent inhibitor in structure-based drug design lies within the ability of computational tools to efficiently and accurately dock a ligand into the binding cavity of the target protein. Here we report the computational characterization of Trypanosoma brucei pteridine reductase (Tb-PR) active-site using twenty-four high-resolution co-crystal structures with various drugs. Structurally, the Tb-PR active site can be grouped in two clusters; one with high Root Mean Square Deviation (RMSD) of atomic positions and another with low RMSD of atomic positions. These clusters provide fresh insight for rational drug design against Tb-PR. Henceforth, the effect of several factors on docking accuracy, including ligand and protein flexibility were analyzed using Fred. Results: The online server was used to analyze the side chain flexibility and four proteins were selected on the basis of results. The proteins were subjected to small-scale virtual screening using 85 compounds, and statistics were calculated using Bedroc and roc curves. The enrichment factor was also calculated for the proteins and scoring functions. The best scoring function was used to understand the ligand protein interactions with top common compounds of four proteins. In addition, we made a 3D structural comparison between the active site of Tb-PR and Leishmania major pteridine reductase (Lm- PR). We described key structural differences between Tb-PR and Lm-PR that can be exploited for rational drug design against these two human parasites. Conclusion: The results indicated that relying just on re-docking and cross-docking experiments for virtual screening of libraries isn’t enough and results might be misleading. Hence it has been suggested that small scale virtual screening should be performed prior to large scale screening.

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Kimuda, Magambo Phillip, Dustin Laming, Heinrich C. Hoppe und Özlem Tastan Bishop. „Identification of Novel Potential Inhibitors of Pteridine Reductase 1 in Trypanosoma brucei via Computational Structure-Based Approaches and in Vitro Inhibition Assays“. Molecules 24, Nr. 1 (01.01.2019): 142. http://dx.doi.org/10.3390/molecules24010142.

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Pteridine reductase 1 (PTR1) is a trypanosomatid multifunctional enzyme that provides a mechanism for escape of dihydrofolate reductase (DHFR) inhibition. This is because PTR1 can reduce pterins and folates. Trypanosomes require folates and pterins for survival and are unable to synthesize them de novo. Currently there are no anti-folate based Human African Trypanosomiasis (HAT) chemotherapeutics in use. Thus, successful dual inhibition of Trypanosoma brucei dihydrofolate reductase (TbDHFR) and Trypanosoma brucei pteridine reductase 1 (TbPTR1) has implications in the exploitation of anti-folates. We carried out molecular docking of a ligand library of 5742 compounds against TbPTR1 and identified 18 compounds showing promising binding modes. The protein-ligand complexes were subjected to molecular dynamics to characterize their molecular interactions and energetics, followed by in vitro testing. In this study, we identified five compounds which showed low micromolar Trypanosome growth inhibition in in vitro experiments that might be acting by inhibition of TbPTR1. Compounds RUBi004, RUBi007, RUBi014, and RUBi018 displayed moderate to strong antagonism (mutual reduction in potency) when used in combination with the known TbDHFR inhibitor, WR99210. This gave an indication that the compounds might inhibit both TbPTR1 and TbDHFR. RUBi016 showed an additive effect in the isobologram assay. Overall, our results provide a basis for scaffold optimization for further studies in the development of HAT anti-folates.

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Cummins, Peter L., und Jill E. Gready. „Prediction of Relative Binding Constants of Cofactors and Designed Ligands to Dihydrofolate Reductase by Computer Simulation“. Pteridines 3, Nr. 1-2 (Februar 1991): 137–39. http://dx.doi.org/10.1515/pteridines.1991.3.12.137.

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8

Fischer, B., A. Schafer, K. Hegetschweiler und M. Viscontini. „Iron and Terahydropterin Complex with 1,3,5-Triamino-2,4,6-trihydroxycydohexane as Ligand“. Pteridines 6, Nr. 3 (August 1995): 87–89. http://dx.doi.org/10.1515/pteridines.1995.6.3.87.

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Ishii, Masakazu, Shunichi Shimizu, Kazuhiro Shiota, Yuji Kiuchi und Toshinori Yamamoto. „Troglitazone Stimulates the Insulin-induced Tetrahydrobiopterin Synthesis In Vascular Endothelial Cells“. Pteridines 11, Nr. 4 (November 2000): 137–41. http://dx.doi.org/10.1515/pteridines.2000.11.4.137.

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Abstract We investigated the effects of troglitazone, which is a ligand of nuclear transcription factor peroxisome proliferator- activated receptor-γ (PPAR-γ), on insulin-induced tetrahydrobiopterin (BH4) synthesis in mouse brain microvascular endothelial cells (MBMECs). BH4 content was determined as biopterin, by reversed-phase high performance liquid chromatography using fluorometric detection. Measurement of mRNA level of GTP cyclohydrolase I (GTPCH), which is a rate-limiting enzyme for de novo BH4 synthesis, was performed by reverse transcription- polymerase chain reaction (RT -PCR). Addition of insulin (10µg/ml) to endothelial cells increased intracellular BH4 content and GTPCH mRNA level, and the insulin-induced increase in BH4 content and GTPCH mRNA level was further stimulated by co-treatment with troglitazone (0.3-3 µM). However, the expression of PPAR-γ mRNA in untreated and insulin-treated endothelial cells was not detected. Moreover, bezafibrate (1-10 µM), a ligand of PPAR-δ, did not affect BH4 synthesis in insulin-treated endothehal cells. These findings suggest that troglitazone stimulates insulin-induced BH4 synthesis in endothelial cells with the induction of GTPCH through PPAR-γ- and PPAR-δ-independent mechanism

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Wirleitner, Barbara, Elisabeth Kowald, Bernhard Widner, Ulrike Ortner, Gabriele Baier-Bitterlich, Norbert Sepp und Dietmar Fuchs. „Soluble Fas ligand and neopterin in patients with systemic and cutaneous discoid lupus erythematosus“. Pteridines 11, Nr. 3 (August 2000): 85–89. http://dx.doi.org/10.1515/pteridines.2000.11.3.85.

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SummaryEvidence accumulates suggesting that the pathogenesis in systemic lupus erythematosus (SLE) is associated with modulations in the Fas/FasL system. Serum concentrations of soluble Fas ligand (sFasL) were found to be elevated in patients with SLE. In this study we wanted to determine the levels of sFasL and the status of immune activation - monitored by neopterin secretion - in patients with SLE and cutaneous discoid lupus erythematosus (CDLE). Sixty-five serum samples were assayed. We found elevated concentrations of sFasL in patients with SLE and CDLE. The levels of sFasL in COLE patients were significant lower compared to SLE patients. Neopterin concentrations in serum were found to be slightly increased in patients with CDLE. Compared to patients with SLE, activation of the immune system was significant lower in COLE. Taken together, we found d evated levels of sFasL in patients with SLE as well as CDLE, connected with ar activation of the immune system and thereby increased concentration of neopterin in serum.

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Ghosh, Suparna, und Seung Joo Cho. „Binding Studies and Lead Generation of Pteridin-7(8H)-one Derivatives Targeting FLT3“. International Journal of Molecular Sciences 23, Nr. 14 (12.07.2022): 7696. http://dx.doi.org/10.3390/ijms23147696.

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Ligand modification by substituting chemical groups within the binding pocket is a popular strategy for kinase drug development. In this study, a series of pteridin-7(8H)-one derivatives targeting wild-type FMS-like tyrosine kinase-3 (FLT3) and its D835Y mutant (FL3D835Y) were studied using a combination of molecular modeling techniques, such as docking, molecular dynamics (MD), binding energy calculation, and three-dimensional quantitative structure-activity relationship (3D-QSAR) studies. We determined the protein–ligand binding affinity by employing molecular mechanics Poisson–Boltzmann/generalized Born surface area (MM-PB/GBSA), fast pulling ligand (FPL) simulation, linear interaction energy (LIE), umbrella sampling (US), and free energy perturbation (FEP) scoring functions. The structure–activity relationship (SAR) study was conducted using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA), and the results were emphasized as a SAR scheme. In both the CoMFA and CoMSIA models, satisfactory correlation statistics were obtained between the observed and predicted inhibitory activity. The MD and SAR models were co-utilized to design several new compounds, and their inhibitory activities were anticipated using the CoMSIA model. The designed compounds with higher predicted pIC50 values than the most active compound were carried out for binding free energy evaluation to wild-type and mutant receptors using MM-PB/GBSA, LIE, and FEP methods.

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Hunter, W. N., M. S. Alphey, C. S. Bond und A. W. Schüttelkopf. „Targeting metabolic pathways in microbial pathogens: oxidative stress and anti-folate drug resistance in trypanosomatids“. Biochemical Society Transactions 31, Nr. 3 (01.06.2003): 607–10. http://dx.doi.org/10.1042/bst0310607.

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The large quantity of genomic, biochemical and metabolic data on microbial pathogens provides information that helps us to select biological problems of interest and to identify targets, metabolic pathways or constituent enzymes, for therapeutic intervention. One area of potential use in developing novel anti-parasitic agents concerns the regulation of oxidative stress, and we have targeted the trypanothione peroxidase pathway in this respect. In order to characterize this pathway, we have determined crystal structures for each of its components, and are now studying enzyme–ligand complexes of the first enzyme, trypanothione reductase. Also with regard to trypanosomatids, a question that arose was: why do anti-folates not provide useful therapies? The enzyme pteridine reductase has been shown to contribute to anti-folate drug resistance, and we have determined the enzyme structure and mechanism to understand this aspect of drug resistance.

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Herrera-Acevedo, Chonny, Areli Flores-Gaspar, Luciana Scotti, Francisco Jaime Bezerra Mendonça-Junior, Marcus Tullius Scotti und Ericsson Coy-Barrera. „Identification of Kaurane-Type Diterpenes as Inhibitors of Leishmania Pteridine Reductase I“. Molecules 26, Nr. 11 (21.05.2021): 3076. http://dx.doi.org/10.3390/molecules26113076.

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The current treatments against Leishmania parasites present high toxicity and multiple side effects, which makes the control and elimination of leishmaniasis challenging. Natural products constitute an interesting and diverse chemical space for the identification of new antileishmanial drugs. To identify new drug options, an in-house database of 360 kauranes (tetracyclic diterpenes) was generated, and a combined ligand- and structure-based virtual screening (VS) approach was performed to select potential inhibitors of Leishmania major (Lm) pteridine reductase I (PTR1). The best-ranked kauranes were employed to verify the validity of the VS approach through LmPTR1 enzyme inhibition assay. The half-maximal inhibitory concentration (IC50) values of selected bioactive compounds were examined using the random forest (RF) model (i.e., 2β-hydroxy-menth-6-en-5β-yl ent-kaurenoate (135) and 3α-cinnamoyloxy-ent-kaur-16-en-19-oic acid (302)) were below 10 μM. A compound similar to 302, 3α-p-coumaroyloxy-ent-kaur-16-en-19-oic acid (302a), was also synthesized and showed the highest activity against LmPTR1. Finally, molecular docking calculations and molecular dynamics simulations were performed for the VS-selected, most-active kauranes within the active sites of PTR1 hybrid models, generated from three Leishmania species that are known to cause cutaneous leishmaniasis in the new world (i.e., L. braziliensis, L. panamensis, and L. amazonensis) to explore the targeting potential of these kauranes to other species-dependent variants of this enzyme.

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Baisya, Siddhartha S., und Parag S. Roy. „Crystal structure of (2-amino-7-methyl-4-oxidopteridine-6-carboxylato-κ3O4,N5,O6)aqua(1,10-phenanthroline-κ2N,N′)copper(II) trihydrate“. Acta Crystallographica Section E Structure Reports Online 70, Nr. 11 (18.10.2014): 348–51. http://dx.doi.org/10.1107/s1600536814022302.

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In the title compound, [Cu(C8H5N5O3)(C12H8N2)(H2O)]·3H2O, the CuIIcation isO,N,O′-chelated by the 2-amino-7-methyl-4-oxidopteridine-6-carboxylate anion andN,N′-chelated by the 1,10-phenanthroline (phen) ligand. A water molecule further coordinates to the CuIIcation to complete the elongated distorted octahedral coordination geometry. In the molecule, the pteridine ring system is essentially planar [maximum deviation = 0.055 (4) Å], and its mean plane is nearly perpendicular to the phen ring system [dihedral angle = 85.97 (3)°]. In the crystal, N—H...O, O—H...N and O—H...·O hydrogen bonds, as well as weak C—H...O hydrogen bonds and C—H...π interactions, link the complex molecules and lattice water molecules into a three-dimensional supramolecular architecture. Extensive π–π stacking between nearly parallel aromatic rings of adjacent molecules are also observed, the centroid-to-centroid distances being 3.352 (2), 3.546 (3), 3.706 (3) and 3.744 (3) Å.

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Jiménez-Pulido, Sonia B., Fátima M. Linares-Ordóñez und Miguel N. Moreno-Carretero. „Novel coordination behavior of a pteridine-benzoylhydrazone ligand (BZLMH): Theoretical calculations, XRD structures and luminescence studies“. Polyhedron 28, Nr. 13 (September 2009): 2641–48. http://dx.doi.org/10.1016/j.poly.2009.05.061.

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Santucci, Matteo, Rosaria Luciani, Eleonora Gianquinto, Cecilia Pozzi, Flavio di Pisa, Lucia dello Iacono, Giacomo Landi et al. „Repurposing the Trypanosomatidic GSK Kinetobox for the Inhibition of Parasitic Pteridine and Dihydrofolate Reductases“. Pharmaceuticals 14, Nr. 12 (30.11.2021): 1246. http://dx.doi.org/10.3390/ph14121246.

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Three open-source anti-kinetoplastid chemical boxes derived from a whole-cell phenotypic screening by GlaxoSmithKline (Tres Cantos Anti-Kinetoplastid Screening, TCAKS) were exploited for the discovery of a novel core structure inspiring new treatments of parasitic diseases targeting the trypansosmatidic pteridine reductase 1 (PTR1) and dihydrofolate reductase (DHFR) enzymes. In total, 592 compounds were tested through medium-throughput screening assays. A subset of 14 compounds successfully inhibited the enzyme activity in the low micromolar range of at least one of the enzymes from both Trypanosoma brucei and Lesihmania major parasites (pan-inhibitors), or from both PTR1 and DHFR-TS of the same parasite (dual inhibitors). Molecular docking studies of the protein–ligand interaction focused on new scaffolds not reproducing the well-known antifolate core clearly explaining the experimental data. TCMDC-143249, classified as a benzenesulfonamide derivative by the QikProp descriptor tool, showed selective inhibition of PTR1 and growth inhibition of the kinetoplastid parasites in the 5 μM range. In our work, we enlarged the biological profile of the GSK Kinetobox and identified new core structures inhibiting selectively PTR1, effective against the kinetoplastid infectious protozoans. In perspective, we foresee the development of selective PTR1 and DHFR inhibitors for studies of drug combinations.

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Jiménez-Pulido, Sonia B., Fátima M. Linares-Ordóñez, Miguel N. Moreno-Carretero und Miguel Quirós-Olozábal. „Versatile Coordinative Abilities of a New Hybrid Pteridine−Thiosemicarbazone Ligand: Crystal Structure, Spectroscopic Characterization, and Luminescent Properties“. Inorganic Chemistry 47, Nr. 3 (Februar 2008): 1096–106. http://dx.doi.org/10.1021/ic701994s.

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Jedwabny, Wiktoria, Joanna Panecka-Hofman, Edyta Dyguda-Kazimierowicz, Rebecca C. Wade und W. Andrzej Sokalski. „Application of a simple quantum chemical approach to ligand fragment scoring for Trypanosoma brucei pteridine reductase 1 inhibition“. Journal of Computer-Aided Molecular Design 31, Nr. 8 (07.07.2017): 715–28. http://dx.doi.org/10.1007/s10822-017-0035-4.

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Er-rajy, Mohammed, Mohamed El fadili, Hamada Imtara, Aamir Saeed, Abid Ur Rehman, Sara Zarougui, Shaef A. Abdullah, Ahmad Alahdab, Mohammad Khalid Parvez und Menana Elhallaoui. „3D-QSAR Studies, Molecular Docking, Molecular Dynamic Simulation, and ADMET Proprieties of Novel Pteridinone Derivatives as PLK1 Inhibitors for the Treatment of Prostate Cancer“. Life 13, Nr. 1 (02.01.2023): 127. http://dx.doi.org/10.3390/life13010127.

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Overexpression of polo-like kinase 1 (PLK1) has been found in many different types of cancers. With its essential role in cell proliferation, PLK1 has been determined to be a broad-spectrum anti-cancer target. In this study, 3D-QSAR, molecular docking, and molecular dynamics (MD) simulations were applied on a series of novel pteridinone derivatives as PLK1 inhibitors to discover anti-cancer drug candidates. In this work, three models—CoMFA (Q² = 0.67, R² = 0.992), CoMSIA/SHE (Q² = 0.69, R² = 0.974), and CoMSIA/SEAH (Q² = 0.66, R² = 0.975)—of pteridinone derivatives were established. The three models that were established gave Rpred2 = 0.683, Rpred 2= 0.758, and Rpred 2= 0.767, respectively. Thus, the predictive abilities of the three proposed models were successfully evaluated. The relations between the different champs and activities were well-demonstrated by the contour chart of the CoMFA and CoMSIA/SEAH models. The results of molecular docking indicated that residues R136, R57, Y133, L69, L82, and Y139 were the active sites of the PLK1 protein (PDB code: 2RKU), in which the more active ligands can inhibit the enzyme of PLK1. The results of the molecular dynamic MD simulation diagram were obtained to reinforce the previous molecular docking results, which showed that both inhibitors remained stable in the active sites of the PLK1 protein (PDB code: 2RKU) for 50 ns. Finally, a check of the ADME-Tox properties of the two most active molecules showed that molecular N° 28 could represent a good drug candidate for the therapy of prostate cancer diseases.

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Schüttelkopf, Alexander W., Larry W. Hardy, Stephen M. Beverley und William N. Hunter. „Structures of Leishmania major Pteridine Reductase Complexes Reveal the Active Site Features Important for Ligand Binding and to Guide Inhibitor Design“. Journal of Molecular Biology 352, Nr. 1 (September 2005): 105–16. http://dx.doi.org/10.1016/j.jmb.2005.06.076.

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Sahi, Shakti, Parul Tewatia und Sabari Ghosal. „Leishmania donovani pteridine reductase 1: comparative protein modeling and protein–ligand interaction studies of the leishmanicidal constituents isolated from the fruits of Piper longum“. Journal of Molecular Modeling 18, Nr. 12 (03.07.2012): 5065–73. http://dx.doi.org/10.1007/s00894-012-1508-y.

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Hueso-Ureña, Francisco, Sonia B. Jiménez-Pulido, Maria P. Fernández-Liencres, Manuel Fernández-Gómez und Miguel N. Moreno-Carretero. „A new five-coordinated CuIP2NO2 system: XRD structure of 6-acetyl-1,3,7-trimethyl-pteridine-2,4(1H,3H)-dione and its Cu(i) (N5,O61,O4)-tridentate complex with triphenylphosphine. An AIM study of the nature of metal–ligand bonds“. Dalton Transactions, Nr. 45 (2008): 6461. http://dx.doi.org/10.1039/b807634k.

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Phadke, Shraddha, Devender Pathak und Rakesh Somani. „Design and In silico Studies of 2,5-Disubstituted 1,2,4-Triazole and 1,3,4-Thiadiazole Derivatives as Pteridine Reductase 1 Inhibitors“. Journal of Pharmaceutical Research International, 21.05.2021, 166–78. http://dx.doi.org/10.9734/jpri/2021/v33i29a31575.

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Aims: Design and in silico studies of 2,5-disubstituted triazole and thiadiazole derivatives as Pteridine Reductase 1 inhibitors. With a view to develop effective agents against Leishmaniasis, 2-substituted-5-[(1H-benzimidazol-2yl) methyl] azole derivatives (A1-A12) were designed against the target enzyme Pteridine reductase 1. Methodology: The series was designed by targeting Pteridine reductase 1 which is an enzyme responsible for folate and pterin metabolism. Based on thorough study of the enzyme structure and structural features of ligands required for optimum interaction with the enzyme, a series of 12 compounds consisting of 2,5-disubstituted 1,2,4-triazole and 1,3,4-thiadiazole derivatives was designed. In silico studies were carried out which included docking studies (using V Life software) to understand binding of the compounds with enzyme PTR1, ADMET studies, drug likeness studies for physicochemical properties and bioactivity studies to understand the possible mechanism of action of the compounds. These studies were undertaken using online softwares, molinspiration and admetSAR web servers. Results: Compounds A10 and A12 gave the best docking scores of -59.9765 and -60.4373 respectively that were close to dihydrobiopterin (original substrate). All the compounds complied with Lipinski’s rule of five. Most of the compounds displayed favorable ADMET properties. Conclusion: The 2,5-disubstituted 1,2,4-triazole and 1,3,4-thiadiazole derivatives exhibited good binding affinity for PTR1 enzyme (PDB code: 1E92). The docking scores indicated that enzyme binding may be governed by the nature and size of the substituents on the azole ring. The compounds display well-defined drug-like and pharmacokinetic properties based on Lipinski’s rule of five with additional physicochemical and ADMET parameters. Bioactivity studies suggested the possible drug mechanism as enzyme inhibition. Hence, this study provides evidence for consideration of valuable ligands in 2,5-disubstituted 1,2,4-triazole and 1,3,4-thiadiazole derivatives as potential pteridine reductase 1 inhibitor and further in vitro and in vivo investigations may prove its therapeutic potential.

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„Automated site-directed drug design : the formation of molecular templates in primary structure generation“. Proceedings of the Royal Society of London. B. Biological Sciences 236, Nr. 1283 (22.03.1989): 141–62. http://dx.doi.org/10.1098/rspb.1989.0018.

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In this paper the spacer skeleton concept is used to produce molecular graphs of putative ligands for binding sites. The skeletons are transformed into molecular templates within the constraints of the accessible surface of the ligand-binding site. A distance-matrix method is used to compare ligand points with vertices of the spacer skeleton through a permutation of all possible correspondences. A tolerance parameter is used to screen for poor matches. As a result, a small number of matched vertices and ligand points are produced. These are fitted into the site by a constrained optimization routine using an analytical function. Ligand points fall within the site and are optimally positioned adjacent to the corresponding site points; other vertices of the spacer skeleton lying beneath the accessible surface of the site are clipped off. A molecular template is thereby formed with its vertices linked to the ligand points. The final step is to verify that the bonding integrity of the skeleton remains. The computational methods outlined in this paper have been tested at two binding sites: the pteridine binding site in dihydrofolate reductase and the amidinophenylpyruvate site of trypsin. Molecular graphs for both sites were generated automatically; they showed strong similarity to those of the natural ligands.

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Neda Adibpour. „In silico designing selective inhibitor of drugs, medicinal plants compounds and experimental ligands for pteridine reductase targeting visceral leishmaniasis“. African Journal of Microbiology Research 6, Nr. 5 (09.02.2012). http://dx.doi.org/10.5897/ajmr-11-738.

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Chinedu, Shalom N., Mercy Bella-Omunagbe, Esther Okafor, Rufus Afolabi und Ezekiel Adebiyi. „Computational Studies on 6-Pyruvoyl Tetrahydropterin Synthase (6-PTPS) of Plasmodium falciparum“. Bioinformatics and Biology Insights 18 (Januar 2024). http://dx.doi.org/10.1177/11779322241230214.

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6-Pyruvoyl tetrahydropterin synthase (6-PTPS) is a lyase involved in the synthesis of tetrahydrobiopterin. In Plasmodium species where dihydroneopterin aldolase (DHNA) is absent, it acts in the folate biosynthetic pathway necessary for the growth and survival of the parasite. The 6-pyruvoyl tetrahydropterin synthase of Plasmodium falciparum ( PfPTPS) has been identified as a potential antimalarial drug target. This study identified potential inhibitors of PfPTPS using molecular docking techniques. Molecular docking and virtual screening of 62 compounds including the control to the deposited Protein Data Bank (PDB) structure was carried out using AutoDock Vina in PyRx. Five of the compounds, N,N-dimethyl- N’-[4-oxo-6-(2,2,5-trimethyl-1,3-dioxolan-4-yl)-3H-pteridin-2-yl]methanimidamide (140296439), 2-amino-6-[(1R)-3-cyclohexyl-1-hydroxypropyl]-3H-pteridin-4-one (140296495), 2-(2,3-dihydroxypropyl)-8,9-dihydro-6H-pyrimido[2,1-b]pteridine-7,11-dione (144380406), 2-(dimethylamino)-6-[(2,2-dimethyl-1,3-dioxolan-4-yl)-hydroxymethyl]-3H-pteridin-4-one (135573878), and [1-acetyloxy-1-(2-methyl-4-oxo-3H-pteridin-6-yl)propan-2-yl] acetate (136075207), showed better binding affinity than the control ligand, biopterin (135449517), and were selected and screened. Three conformers of 140296439 with the binding energy of −7.2, −7.1, and −7.0 kcal/mol along with 140296495 were better than the control at −5.7 kcal/mol. In silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies predicted good pharmacokinetic properties of all the compounds while reporting a high risk of irritant toxicity in 140296439 and 144380406. The study highlights the five compounds, 140296439, 140296495, 144380406, 135573878 and 136075207, as potential inhibitors of PfPTPS and possible compounds for antimalarial drug development.

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Panecka-Hofman, Joanna, und Ina Poehner. „Structure and dynamics of pteridine reductase 1: the key phenomena relevant to enzyme function and drug design“. European Biophysics Journal, 22.08.2023. http://dx.doi.org/10.1007/s00249-023-01677-6.

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AbstractPteridine reductase 1 (PTR1) is a folate and pterin pathway enzyme unique for pathogenic trypanosomatids. As a validated drug target, PTR1 has been the focus of recent research efforts aimed at finding more effective treatments against human parasitic diseases such as leishmaniasis or sleeping sickness. Previous PTR1-centered structural studies highlighted the enzyme characteristics, such as flexible regions around the active site, highly conserved structural waters, and species-specific differences in pocket properties and dynamics, which likely impacts the binding of natural substrates and inhibitors. Furthermore, several aspects of the PTR1 function, such as the substrate inhibition phenomenon and the level of ligand binding cooperativity in the enzyme homotetramer, likely related to the global enzyme dynamics, are poorly known at the molecular level. We postulate that future drug design efforts could greatly benefit from a better understanding of these phenomena through studying both the local and global PTR1 dynamics. This review highlights the key aspects of the PTR1 structure and dynamics relevant to structure-based drug design that could be effectively investigated by modeling approaches. Particular emphasis is given to the perspective of molecular dynamics, what has been accomplished in this area to date, and how modeling could impact the PTR1-targeted drug design in the future.

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