Synthesis of novel quinoline‐thiosemicarbazide hybrids and evaluation of their biological activities, molecular docking, molecular dynamics, pharmacophore model studies, and ADME‐Tox properties

mGluR5, which belongs to the G-protein-coupled receptor superfamily, is believed to be associated with many human diseases, such as a wide range of neurological disorders, gastroesophageal reflux disease, and cancer. Comparing with compounds that target on the orthosteric binding site, significant roles have been established for mGluR5 negative allosteric modulators (NAMs) due to their higher subtype selectivity and more suitable pharmacokinetic profiles. Nevertheless, to date, none of them have come to market for various reasons. In this study, a 3D quantitative pharmacophore model was generated by using the HypoGen module in Discovery Studio 4.0. With several validation methods ultilized, the optimal pharmacophore model Hypo2 was selected to discover potential mGluR5 NAMs from natural products. Two hundred and seventeen potential NAMs were obtained after being filtered by Lipinski’s rule (≥4). Then, molecular docking was used to refine the pharmacophore-based screening results and analyze the binding mode of NAMs and mGluR5. Three compounds, aglaiduline, 5-O-ethyl-hirsutanonol, and yakuchinone A, with good ADMET properties, acceptable Fit value and estimated value, and high docking score, were reserved for a molecular dynamics simulation study. All of them have stability of ligand binding. From our computational results, there might exhibit drug-like negative allosteric moderating effects on mGluR5 in these natural products. This work provides a reliable method for discovering mGluR5 NAMs from natural products.

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Investigations on the mechanisms of interactions between matrix metalloproteinase 9 and its flavonoid inhibitors using a combination of molecular docking, hybrid quantum mechanical/molecular mechanical calculations, and molecular dynamics simulations

Canadian Journal of Chemistry ◽

10.1139/cjc-2014-0180 ◽

2014 ◽

Vol 92 (9) ◽

pp. 821-830 ◽

Cited By ~ 8

Author(s):

Zhi-Guang Zhou ◽

Qi-Zheng Yao ◽

Dong Lei ◽

Qing-Qing Zhang ◽

Ji Zhang

Keyword(s):

Molecular Dynamics ◽

Molecular Docking ◽

Molecular Dynamics Simulations ◽

Biological Activities ◽

Dynamics Simulation ◽

Quantum Mechanical ◽

Free Energies ◽

Hydrogen Bond Networks ◽

Dynamics Simulations ◽

Binding Free Energies

Many experimental studies have found that flavonoids can inhibit the activities of matrix metalloproteinases (MMPs), but the relevant mechanisms are still unclear. In this paper, the interaction mechanisms of MMP-9 with its five flavonoid inhibitors are investigated using a combination of molecular docking, hybrid quantum mechanical and molecular mechanical (QM/MM) calculations, and molecular dynamics simulations. The molecular dynamics simulation results show a good linear correlation between the calculated binding free energies of QM/MM−Poisson–Boltzmann surface area (PBSA) and the experimental −log(EC50) regarding the studied five flavonoids on MMP-9 inhibition in explicit solvent. It is found that compared with the MM−PBSA method, the QM/MM−PBSA method can obviously improve the accuracy for the calculated binding free energies. The predicted binding modes of the five flavonoid−MMP-9 complexes reveal that the different hydrogen bond networks can form besides producing the Zn−O coordination bonds, which can reasonably explain previous experimental results. The agreement between our calculated results and the previous experimental facts indicates that the force field parameters used here are effective and reliable for investigating the systems of flavonoid−MMP-9 interactions, and thus, these simulations and analyses could be reproduced for the other related systems involving protein−ligand interactions. This paper may be helpful for designing the new MMP-9 inhibitors having higher biological activities by carrying out the structural modifications of flavonoid molecules.

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Virtual screening of curcumin analogues as DYRK2 inhibitor: Pharmacophore analysis, molecular docking and dynamics, and ADME prediction

F1000Research ◽

10.12688/f1000research.28040.1 ◽

2021 ◽

Vol 10 ◽

pp. 394

Author(s):

La Ode Aman ◽

Rahmana Emran Kartasasmita ◽

Daryono Hadi Tjahjono

Keyword(s):

Molecular Dynamics ◽

Molecular Docking ◽

Pharmacophore Model ◽

Binding Pocket ◽

26S Proteasome ◽

Dynamics Simulation ◽

Pharmacophore Modelling ◽

Curcumin Analogues ◽

Adme Prediction ◽

Pharmacokinetic Properties

Background: Curcumin reduces the proliferation of cancer cells through inhibition of the DYRK2 enzyme, which is a positive regulator of the 26S proteasome. Methods: In the present work, curcumin analogues have been screened from the MolPort database using a pharmacophore model that comprised a ligand-based approach. The result of the screening was then evaluated by molecular docking and molecular dynamics based on binding the free energy of the interaction between each compound with the binding pocket of DYRK2. The hit compounds were then confirmed by absorption, distribution, metabolism, and excretion (ADME) prediction. Results: Screening of 7.4 million molecules from the MolPort database afforded six selected hit compounds. By considering the ADME prediction, three prospective curcumin analogues have been selected. These are: 2‐[2‐(1‐methylpyrazol‐4‐yl)ethyl]‐1H,5H,6H,7H,8H‐imidazo[4,5‐c]azepin‐4‐one (Molport-035-369-361), methyl 4‐(3‐hydroxy‐1,2‐oxazol‐5‐yl)piperidine‐1‐carboxylate (Molport-000-004-273) and (1S)‐1‐[5‐(furan‐3‐carbonyl)‐4H,6H,7H‐pyrazolo[1,5‐a]pyrazin‐2‐yl]ethanol (MolPort-035-585-822). Conclusion: Pharmacophore modelling, combined with molecular docking and molecular dynamics simulation, as well as ADME prediction were successfully applied to screen curcumin analogues from the MolPort database as DYRK2 inhibitors. All selected compounds that have better predicted pharmacokinetic properties than that of curcumin are considered for further study.

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Synthesis, Molecular Docking and Molecular Dynamics Simulation of 2-thioxothiazolidin-4-one derivatives against Gp41

Current HIV Research ◽

10.2174/1570162x18666200903172127 ◽

2020 ◽

Vol 18 ◽

Author(s):

Nahid Tamiz ◽

Tahereh Mostashari-Rad ◽

Aylar Najafipour ◽

Sandra Claes ◽

Dominique Schols ◽

...

Keyword(s):

Molecular Dynamics ◽

Molecular Docking ◽

Biological Activities ◽

Dynamics Simulation ◽

Heptad Repeat ◽

Chemical Interactions ◽

Chemical Structures ◽

In Silico Studies ◽

Anti Hiv ◽

Hiv 1

Introduction: Gp41 and its conserved hydrophobic groove on the N-terminal heptad repeat region are of attractive targets in the design of HIV-1 entry inhibitors. Linearly extended molecules have shown potent anti-HIV-1 activity for their effective interactions with the gp41 binding pocket. Rhodanine ring attached to substituted pyrrole or furan rings has been proved a preferred moiety to be inserted inside the molecular structure of the gp41 inhibitors. Objectives: Based on the previous findings we are going to describe some rhodanine derivatives in which a substituted imidazole ring is introduced in place of the pyrrole or furan rings. The compounds’ flexibility is increased by inserting methylene groups inside the main scaffold. Methods: Molecular docking and molecular dynamics simulations approaches were exploited to investigate the chemical interactions and the stability of the designed ligands-gp41 complex. All compounds were synthesized and their chemical structures were elucidated by 1HNMR, 13CNMR, FTIR and Mass spectroscopy. Biological activities of the compounds against HIV-1 and HIV-2 and their cellular toxicities against the T-lymphocyte (MT-4) cell line were determined. Results: All the designed compounds showed proper and stable chemical interactions with gp41 according to the in silico studies. The results of the biological tests proved none of the compounds active against HIV-1 replication in cell cultures. Conclusion: Since all the studied compounds were potently toxic for the host cell; it was therefore not possible to assess their anti-HIV activities.

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Identification of Potential inhibitors for Hematopoietic Prostaglandin D2 Synthase: Computational Modeling and Molecular Dynamics Simulations

10.1101/2021.08.19.456954 ◽

2021 ◽

Author(s):

Satyajit Beura ◽

Prabhakar Chetti

Keyword(s):

Molecular Dynamics ◽

Molecular Docking ◽

Virtual Screening ◽

Molecular Dynamics Simulations ◽

Binding Free Energy ◽

Pharmacophore Model ◽

Prostaglandin D2 ◽

Prostaglandin D2 Synthase ◽

Dynamics Simulations ◽

Potential Inhibitors

To design a new therapeutic agent for Hematopoietic Prostaglandin D2 synthase (hPGDS), a set of 60 molecules with different molecular scaffolds were (range of pIC50 values are from 8.301 to 3.932) considered to create a pharmacophore model. Further, identification of potential hPGDS inhibitors were carried out by using virtual screening with different databases (from 15,74,182 molecules). The Molecular screening was performed using different sequential methods right from Pharmacophore based virtual screening, molecular docking, MM-GBSAstudies, ADME property analysis and molecular dynamics simulations using Maestro11.9 software. Based on the best pharmacophore model (ADRR_1), the resultant set of 18,492 molecules were screened. The preliminarily screened molecules were subjected to molecular docking (PDB_ID: 2CVD) methods. A set of 27 molecules was screened from the resultant molecular docking outcomes (360 molecules) based on binding free energy (ΔGbind) and Lipinskis rule of five. Out of 27 molecules, 4 were selected visual data analysis and further subjected to molecular dynamics (MD) simulation study. Outcomes of the present study conclude with three new proposed molecules (SP1, SP2 and SP10) which show a good range of interaction with human hPGDS enzyme in comparison to the marketed compounds i.e., HQL-79, TFC-007, HPGDS inhibitor I and TAS-204.

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Design and screening of FAK, CDK 4/6 dual inhibitors by pharmacophore model, molecular docking, and molecular dynamics simulation

Journal of Biomolecular Structure and Dynamics ◽

10.1080/07391102.2020.1786458 ◽

2020 ◽

pp. 1-10

Author(s):

Chuance Sun ◽

Lijun Feng ◽

Xiaohua Sun ◽

Rilei Yu ◽

Congmin Kang

Keyword(s):

Molecular Dynamics ◽

Molecular Docking ◽

Molecular Dynamics Simulation ◽

Pharmacophore Model ◽

Dynamics Simulation ◽

Dual Inhibitors

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Molecular docking and pharmacophore model studies of Rho kinase inhibitors

Molecular Simulation ◽

10.1080/08927022.2011.554548 ◽

2011 ◽

Vol 37 (06) ◽

pp. 488-494 ◽

Cited By ~ 4

Author(s):

Dong-Hua Wang ◽

Wan-Lu Qu ◽

Liu-Qing Shi ◽

Jing Wei

Keyword(s):

Molecular Docking ◽

Kinase Inhibitors ◽

Rho Kinase ◽

Pharmacophore Model ◽

Model Studies ◽

Rho Kinase Inhibitors

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Structure-Based Pharmacophore Modeling, Virtual Screening, Molecular Docking, ADMET, and Molecular Dynamics (MD) Simulation of Potential Inhibitors of PD-L1 from the Library of Marine Natural Products

Marine Drugs ◽

10.3390/md20010029 ◽

2021 ◽

Vol 20 (1) ◽

pp. 29

Author(s):

Lianxiang Luo ◽

Ai Zhong ◽

Qu Wang ◽

Tongyu Zheng

Keyword(s):

Molecular Dynamics ◽

Natural Products ◽

Molecular Docking ◽

Virtual Screening ◽

Marine Natural Products ◽

Md Simulation ◽

Pharmacophore Model ◽

Pharmacophore Modeling ◽

Dynamics Simulation ◽

Stable Conformation

Background: In the past decade, several antibodies directed against the PD-1/PD-L1 interaction have been approved. However, therapeutic antibodies also exhibit some shortcomings. Using small molecules to regulate the PD-1/PD-L1 pathway may be another way to mobilize the immune system to fight cancer. Method: 52,765 marine natural products were screened against PD-L1(PDBID: 6R3K). To identify natural compounds, a structure-based pharmacophore model was generated, following by virtual screening and molecular docking. Then, the absorption, distribution, metabolism, and excretion (ADME) test was carried out to select the most suitable compounds. Finally, molecular dynamics simulation was also performed to validate the binding property of the top compound. Results: Initially, 13 small marine molecules were screened based on the pharmacophore model. Then, two compounds were selected for further evaluation based on the molecular docking scores. After ADME and toxicity studies, molecule 51320 was selected for further verification. By molecular dynamics analysis, molecule 51320 maintains a stable conformation with the target protein, so it has the chance to become an inhibitor of PD-L1. Conclusions: Through structure-based pharmacophore modeling, virtual screening, molecular docking, ADMET approaches, and molecular dynamics (MD) simulation, the marine natural compound 51320 can be used as a small molecule inhibitor of PD-L1.

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In Silico Exploration of Novel Tubulin Inhibitors: A Combination of Docking and Molecular Dynamics Simulations, Pharmacophore Modeling, and Virtual Screening

Computational and Mathematical Methods in Medicine ◽

10.1155/2022/4004068 ◽

2022 ◽

Vol 2022 ◽

pp. 1-11

Author(s):

Farzin Hadizadeh ◽

Razieh Ghodsi ◽

Salimeh Mirzaei ◽

Amirhossein Sahebkar

Keyword(s):

Molecular Dynamics ◽

Molecular Docking ◽

Critical Role ◽

Human Tumor ◽

Pharmacophore Model ◽

Pharmacophore Modeling ◽

Microtubule Network ◽

Acquired Drug Resistance ◽

Tubulin Inhibitors ◽

Microtubule Targeting Agents

Microtubules play a critical role in mitosis and cell division and are regarded as an excellent target for anticancer therapy. Although microtubule-targeting agents have been widely used in the clinical treatment of different human cancers, their clinical application in cancer therapy is limited by both intrinsic and acquired drug resistance and adverse toxicities. In a previous work, we synthesized compound 9IV-c, ((E)-2-(3,4-dimethoxystyryl)-6,7,8-trimethoxy-N-(3,4,5-trimethoxyphenyl)quinoline-4-amine) that showed potent activity against multiple human tumor cell lines, by targeting spindle formation and/or the microtubule network. Accordingly, in this study, to identify potent tubulin inhibitors, at first, molecular docking and molecular dynamics studies of compound 9IV-c were performed into the colchicine binding site of tubulin; then, a pharmacophore model of the 9IV-c-tubulin complex was generated. The pharmacophore model was then validated by Güner–Henry (GH) scoring methods and receiver operating characteristic (ROC) analysis. The IBScreen database was searched by using this pharmacophore model as a screening query. Finally, five retrieved compounds were selected for molecular docking studies. These efforts identified two compounds (b and c) as potent tubulin inhibitors. Investigation of pharmacokinetic properties of these compounds (b and c) and compound 9IV-c displayed that ligand b has better drug characteristics compared to the other two ligands.

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