Potential Inhibitors of Fascin From A Database of Marine Natural Products: A Virtual Screening and Molecular Dynamics Study

Marine nature products are unique compounds that are produced by the marine environment including plants, animals, and microorganisms. The wide diversity of marine natural products have great potential and are versatile in terms of drug discovery. In this paper, we use state-of-the-art computational methods to discover inhibitors from marine natural products to block the function of Fascin, an overexpressed protein in various cancers. First, virtual screening (pharmacophore model and molecular docking) was carried out based on a marine natural products database (12015 molecules) and provided eighteen molecules that could potentially inhibit the function of Fascin. Next, molecular mechanics generalized Born surface area (MM/GBSA) calculations were conducted and indicated that four molecules have higher binding affinities than the inhibitor NP-G2-029, which was validated experimentally. ADMET analyses of pharmacokinetics demonstrated that one of the four molecules does not match the criterion. Finally, ligand Gaussian accelerated molecular dynamics (LiGaMD) simulations were carried out to validate the three inhibitors binding to Fascin stably. In addition, dynamic interactions between protein and ligands were analyzed systematically. Our study will accelerate the development of the cancer drugs targeting Fascin.

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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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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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Can natural products stop the SARS-CoV-2 virus? A docking and molecular dynamics study of a natural product database

Future Medicinal Chemistry ◽

10.4155/fmc-2020-0248 ◽

2021 ◽

Author(s):

Jurica Novak ◽

Hrvoje Rimac ◽

Shivananda Kandagalla ◽

Maria A Grishina ◽

Vladimir A Potemkin

Keyword(s):

Molecular Dynamics ◽

Natural Products ◽

Virtual Screening ◽

Molecular Dynamics Simulations ◽

Natural Product ◽

Binding Sites ◽

Potent Inhibitor ◽

Maturation Process ◽

Dynamics Simulations ◽

Potential Inhibitors

Background: The SARS-CoV-2 3CLpro is one of the primary targets for designing new and repurposing known drugs. Methodology: A virtual screening of molecules from the Natural Product Atlas was performed, followed by molecular dynamics simulations of the most potent inhibitor bound to two conformations of the protease and into two binding sites. Conclusion: Eight molecules with appropriate ADMET properties are suggested as potential inhibitors. The greatest benefit of this study is the demonstration that these ligands can bind in the catalytic site but also to the groove between domains II and III, where they interact with a series of residues which have an important role in the dimerization and the maturation process of the enzyme.

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Repositioning of Etravirine as a Potential CK1ε Inhibitor by Virtual Screening

Pharmaceuticals ◽

10.3390/ph15010008 ◽

2021 ◽

Vol 15 (1) ◽

pp. 8

Author(s):

Luis Córdova-Bahena ◽

Axel A. Sánchez-Álvarez ◽

Angel J. Ruiz-Moreno ◽

Marco A. Velasco-Velázquez

Keyword(s):

Molecular Dynamics ◽

Virtual Screening ◽

Noncovalent Interactions ◽

Antineoplastic Agent ◽

Pharmacophore Model ◽

Hiv Infections ◽

Binding Behavior ◽

Approved Drugs ◽

Potential Inhibitors ◽

Fda Approved Drugs

CK1ε is a key regulator of WNT/β-catenin and other pathways that are linked to tumor progression; thus, CK1ε is considered a target for the development of antineoplastic therapies. In this study, we performed a virtual screening to search for potential CK1ε inhibitors. First, we characterized the dynamic noncovalent interactions profiles for a set of reported CK1ε inhibitors to generate a pharmacophore model, which was used to identify new potential inhibitors among FDA-approved drugs. We found that etravirine and abacavir, two drugs that are approved for HIV infections, can be repurposed as CK1ε inhibitors. The interaction of these drugs with CK1ε was further examined by molecular docking and molecular dynamics. Etravirine and abacavir formed stable complexes with the target, emulating the binding behavior of known inhibitors. However, only etravirine showed high theoretical binding affinity to CK1ε. Our findings provide a new pharmacophore for targeting CK1ε and implicate etravirine as a CK1ε inhibitor and antineoplastic agent.

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Pharmacophore-Guided Identification of Natural Products as Potential Inhibitors of Mycobacterium ulcerans Cystathionine γ-Synthase MetB

Computation ◽

10.3390/computation9030032 ◽

2021 ◽

Vol 9 (3) ◽

pp. 32

Author(s):

Samuel K. Kwofie ◽

Nigel N. O. Dolling ◽

Emmanuel Donkoh ◽

Godwin M. Laryea ◽

Lydia Mosi ◽

...

Keyword(s):

Natural Products ◽

Buruli Ulcer ◽

Pharmacophore Model ◽

Mycobacterium Ulcerans ◽

Bioactive Molecules ◽

Binding Affinities ◽

Dynamics Simulations ◽

Potential Inhibitors ◽

Methionine Synthesis ◽

Poor Efficacy

Buruli ulcer caused by Mycobacterium ulcerans (M. ulcerans) is identified by a pain-free cyst or edema which develops into a massive skin ulcer if left untreated. There are reports of chemoresistance, toxicity, noncompliance, and poor efficacy of current therapeutic options. Previously, we used cheminformatics approaches to identify potential antimycobacterial compounds targeting major receptors in M. ulcerans. In this paper, we sought to identify potential bioactive compounds by targeting Cystathionine gamma-synthase (CGS) MetB, a key receptor involved in methionine synthesis. Inhibition of methionine synthesis restricts the growth of M. ulcerans. Two potent inhibitors Juglone (IC50 0.7 +/− 0.7 µmol/L) and 9-hydroxy-alpha-lapachone (IC50 0.9 +/− 0.1 µmol/L) were used to generate 3D chemical feature pharmacophore model via LigandScout with a score of 0.9719. The validated model was screened against a pre-filtered library of 2530 African natural products. Compounds with fit scores above 66.40 were docked against the structure of CGS to generate hits. Three compounds, namely Gentisic 5-O glucoside (an isolate of African tree Alchornea cordifolia), Isoscutellarein (an isolate of Theobroma plant) and ZINC05854400, were identified as potential bioactive molecules with high binding affinities of −7.1, −8.4 and −8.4 kcal/mol against CGS, respectively. Novel structural insight into the binding mechanisms was elucidated using LigPlot+ and molecular dynamics simulations. All three molecules were predicted to possess antibacterial, anti-ulcerative, and dermatological properties. These compounds have the propensity to disrupt the methionine synthesis mechanisms with the potential of stagnating the growth of M. ulcerans. As a result of reasonably good pharmacological profiling, the three drug-like compounds are potential novel scaffolds that can be optimized into antimycobacterial molecules.

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ENERGY-BASED PHARMACOPHORE MODELING, VIRTUAL SCREENING, AND MOLECULAR DYNAMICS TO IDENTIFY POTENTIAL INHIBITORS FOR GLYCOGEN SYNTHASE KINASE 3 BETA

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2018.v11i2.22962 ◽

2018 ◽

Vol 11 (2) ◽

pp. 181

Author(s):

Sheema Jb ◽

Waheeta Hopper

Keyword(s):

Molecular Dynamics ◽

Wound Healing ◽

Glycogen Synthase ◽

Pharmacophore Model ◽

Pharmacophore Modeling ◽

Glycogen Synthase Kinase ◽

Glycogen Synthase Kinase 3 ◽

Systemic Side Effects ◽

The Stability ◽

Potential Inhibitors

Objective: Glycogen synthase kinase 3 beta (GSK3β) is one of the main targets for wound healing activity. Our objective is to identify novel inhibitors for GSK3β using in silico approach.Methods: Grid-based molecular docking, energy-based pharmacophore (e-pharmacophore) modeling, and molecular dynamics (MD) studies were performed for phytocompounds with GSK3β and compared with standard drugs using Schrodinger software.Results: The glide scores and the molecular interactions of the phytocompounds were well comparable to the standard drugs. The MD was performed for the target bound to the best scoring ligand, entagenic acid. The pharmacophore features of this docked complex were modeled as e-pharmacophore. The constructed e-pharmacophore model was screened against phytocompounds retrieved from literature to identify the ligands with similar pharmacophore features.Conclusion: The glide scores of fukinolic acid, cimicifugic acid, and linarin were −10.99, −8.28, and −7.25 kcal/mol, respectively. The further 50 nanoseconds MD study determined the stability of GSK3β-linarin complex. Nitrofurazone and sulfathiazole drugs can lead to systemic side effects. Hence, it is concluded that linarin could be a potent wound healing compound against GSK3β.

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Structure-based virtual screening for new lead compounds targeted Plasmodium α-tubulin

Faktori eksperimental'noi evolucii organizmiv ◽

10.7124/feeo.v28.1389 ◽

2021 ◽

Vol 28 ◽

pp. 135-139

Author(s):

O. V. Rayevsky ◽

O. M. Demchyk ◽

P. A. Karpov ◽

S. P. Ozheredov ◽

S. I. Spivak ◽

...

Keyword(s):

Virtual Screening ◽

Protein Interaction ◽

Specific Binding ◽

Pharmacophore Model ◽

Computational Prediction ◽

Mitotic Apparatus ◽

Ligand Interaction ◽

Lead Compounds ◽

Key Functional Groups ◽

Potential Inhibitors

Aim. Search for new dinitroaniline and phosphorothioamide compounds, capable of selective binding with Plasmodium α-tubulin, affecting its mitotic apparatus. Methods. Structural biology methods of computational prediction of protein-ligand interaction: molecular docking, molecular dynamics and pharmacophore analysis. Selection of compounds based on pharmacophore characteristics and virtual screening results. Results. The protocol and required structural conditions for target (α-tubulin of P. falciparum) preparation and correct modeling of the ligand-protein interaction (docking and virtual screening) were developed. The generalized pharmacophore model of ligand-protein interaction and key functional groups of ligands responsible for specific binding were identified. Conclusions. Based on results of virtual screening, 22 commercial compounds were selected. Identified compounds proposed as potential inhibitors of Plasmodium mitotic machinery and the base of new antimalarial drugs. Keywords: malaria, Plasmodium, intermolecular interaction, dinitroaniline derived, phosphorothioamidate derived.

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