Computational Discovery of SARS-CoV-2 NSP 16 Drug Candidates Based on Pharmacophore Modeling and Molecular Dynamics Simulation

2021 ◽  
Vol 20 (04) ◽  
pp. 377-390
Author(s):  
Zahra Hesari ◽  
Samaneh Zolghadri ◽  
Sajad Moradi ◽  
Mohsen Shahlaei ◽  
Elham Tazikeh-Lemeski
Keyword(s):  
Molecular Dynamics ◽  
Study Drug ◽  
Pharmacophore Modeling ◽  
Binding Energies ◽  
Dynamics Simulation ◽  
Structural Protein ◽  
Drug Candidates ◽  
Computational Discovery ◽  
Approved Drugs ◽  
Dynamics Simulations

Non-Structural Protein 16 (NSP-16) is one of the most suitable targets for discovery of drugs for corona viruses including SARS-CoV-2. In this study, drug discovery of SARS-CoV-2 nsp-16 has been accomplished by pharmacophore-based virtual screening among some analogs (FDA approved drugs) and marine natural plants (MNP). The comparison of the binding energies and the inhibition constants was determined using molecular docking method. Three compounds including two FDA approved (Ibrutinib, Idelalisib) and one MNP (Kumusine) were selected for further investigation using the molecular dynamics simulations. The results indicated that Ibrutinib and Idelalisib are oral medications while Kumusine, with proper hydrophilic and solubility properties, is an appropriate candidate for nsp-16 inhibitor and can be effective to control COVID-19 disease.

scholarly journals Computational Study on Novel Natural Inhibitors Targeting c-MET

2021 ◽  
Author(s):  
Junliang Ge ◽  
Bo Wu ◽  
Wenzhuo Yang ◽  
Sheng Zhong ◽  
Yuanyuan Hou ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Binding Affinity ◽  
Computational Study ◽  
Developmental Toxicity ◽  
Inhibitory Effect ◽  
Dynamics Simulation ◽  
Drug Candidates ◽  
Zinc Database ◽  
The Stability ◽  
Dynamics Simulations

Abstract Object This study was designed to select ideal lead compounds and preclinical drug candidates with inhibitory effect on c-MET from the drug library (ZINC database).Methods A battery of computer-aided virtual techniques were used to identify possible inhibitors of c-MET. LibDock is applied for structure-based screening followed by ADME (absorption, distribution, metabolic, excretion) and toxicity prediction. Molecular docking was conducted to confirm the binding affinity mechanism between the ligand and c-MET Molecular dynamics simulations were used to assess the stability of ligand-c-MET complexes.Results Two new natural compounds ZINC000005879645 and ZINC000002528509 were found to bind to c-MET in ZINC database, showing higher binding affinity. In addition, they were predicted to have lower rodent carcinogenicity, Ames mutagenicity, developmental toxicity potential, and high tolerance to cytochrome P4502D6. Molecular dynamics simulation shows that ZINC000005879645 and ZINC000002528509 have more favorable potential energies with c-MET, which could exist stably in the natural environment.Conclusion This study suggests that ZINC000005879645 and ZINC000002528509 are ideal latent inhibitors of c-MET targeting. As drug candidates, these two compounds have great security and important implications for the design and improvement of c-MET target drugs.

scholarly journals Natural xanthone compounds as promising drug candidates against COVID-19 - An integrated molecular docking and dynamics simulation study

2020 ◽  
Author(s):  
Shravan Kumar Gunda ◽  
Hima Kumari P ◽  
Gourav Choudhir ◽  
Anuj Kumar ◽  
P B. Kavi Kishor ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Antiviral Agents ◽  
Binding Energies ◽  
Dynamics Simulation ◽  
Lipinski’S Rule ◽  
Drug Candidates ◽  
Main Protease ◽  
Lipinski’S Rule Of Five ◽  
Dynamics Simulations ◽  
Potential Inhibitors

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease2019 (COVID-19). SARS-CoV-2 is known for its high pathogenicity and transmission due to thepresence of polybasic cleavage sites. No specific drug is available for the treatment. To identifythe potential inhibitors, we have performed molecular docking against the SARS-CoV-2 mainprotease (6Y84) with fifteen important natural xanthone compounds. The docking results showedall the compounds exhibited good binding energies and interactions with the main protease. Thevalidation of representative docking complexes through molecular dynamics simulations showedthat xanthones binds with a higher binding affinity and lower free energy than the standardligand with Brasixanthone C and Brasixanthone B on 50 ns. Natural xanthone compounds havealso passed the Absorption, Distribution, Metabolism, and Excretion (ADME) property criteriaas well as Lipinski’s rule of five. The present integrated molecular docking and dynamicssimulations study unveil the use of xanthones as potential antiviral agents against SARS-CoV-2.

scholarly journals Discovery of Novel Tankyrase Inhibitors through Molecular Docking-Based Virtual Screening and Molecular Dynamics Simulation Studies

Molecules ◽  
2020 ◽  
Vol 25 (14) ◽  
pp. 3171 ◽  
Author(s):  
Vladimir P. Berishvili ◽  
Alexander N. Kuimov ◽  
Andrew E. Voronkov ◽  
Eugene V. Radchenko ◽  
Pradeep Kumar ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Virtual Screening ◽  
Molecular Dynamics Simulations ◽  
Binding Energies ◽  
Dynamics Simulation ◽  
Ic50 Values ◽  
Energy Perturbation ◽  
Dynamics Simulations

Tankyrase enzymes (TNKS), a core part of the canonical Wnt pathway, are a promising target in the search for potential anti-cancer agents. Although several hundreds of the TNKS inhibitors are currently known, identification of their novel chemotypes attracts considerable interest. In this study, the molecular docking and machine learning-based virtual screening techniques combined with the physico-chemical and ADMET (absorption, distribution, metabolism, excretion, toxicity) profile prediction and molecular dynamics simulations were applied to a subset of the ZINC database containing about 1.7 M commercially available compounds. Out of seven candidate compounds biologically evaluated in vitro for their inhibition of the TNKS2 enzyme using immunochemical assay, two compounds have shown a decent level of inhibitory activity with the IC50 values of less than 10 nM and 10 μM. Relatively simple scores based on molecular docking or MM-PBSA (molecular mechanics, Poisson-Boltzmann, surface area) methods proved unsuitable for predicting the effect of structural modification or for accurate ranking of the compounds based on their binding energies. On the other hand, the molecular dynamics simulations and Free Energy Perturbation (FEP) calculations allowed us to further decipher the structure-activity relationships and retrospectively analyze the docking-based virtual screening performance. This approach can be applied at the subsequent lead optimization stages.

scholarly journals Assessment of structural peculiarities of glaziovianin A interaction with human α-, β and γ-tubulins

2018 ◽  
Vol 22 ◽  
pp. 340-344
Author(s):  
P. A. Karpov ◽  
S. I. Spivak ◽  
O. V. Rayevsky ◽  
O. Yu. Nyporko ◽  
S. P. Ozheredov ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Protein Interaction ◽  
Protein Complexes ◽  
Binding Energies ◽  
Dynamics Simulation ◽  
Exchange Site ◽  
Ligand Interactions ◽  
Dynamics Simulations ◽  
Alternative Sites

Aim. To determine the features of the ligand-protein interaction of glaziovianin A and human α-, β- and γ-tubulin. Methods. Protein and ligand spatial structure modelling (I-Tasser, Grid), molecular docking (CCDC Gold), molecular dynamics simulation (GROMACS). Results. Using the method of molecular docking in CCDC Gold ligand-protein complexes of glaziovianin A and human α-, β- and γ-tubulin were reconstructed. Studied ligand interactions in GTP/GDP-exchange and colchicine binding sites of different tubulin isotypes. The built ligand-protein complexes were studied using molecular dynamics simulations. Conclusions. Binding of glaziovianin A with human tubulin was confirmed exposing its derivatives as perspective tubulin effectors. The binding energies of ligand-protein interaction confirm higher affinity for β-tubulin molecules, and it was suggested that glazovianin A binding may occur at two alternative sites: GTP/GDP-exchange site and site of colchicine binding. Keywords: tubulin, glaziovianin A, binding, antitumor activity.

scholarly journals Novel Natural Inhibitors Targeting AKT1 by Computational Study

2021 ◽  
Author(s):  
Bo Wu ◽  
Wenzhuo Yang ◽  
Zhiyun Zhang ◽  
Gaojing Dou ◽  
Xiaye Lv ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Computational Study ◽  
Developmental Toxicity ◽  
Inhibitory Effect ◽  
Dynamics Simulation ◽  
Drug Candidates ◽  
Receptor Complexes ◽  
Zinc Database ◽  
Dynamics Simulations ◽  
Potential Inhibitors

Abstract Object: This study was designed to screen ideal lead compounds and drug candidates with an inhibitory effect on AKT1 from the drug library (ZINC database).Methods: A battery of computer-aided virtual techniques were used to identify potential inhibitors of AKT1. LibDock is used for structure-based screening followed by ADME (absorption distribution, metabolic excretion) and toxicity prediction. Molecular dynamics simulations were used to evaluate the stability of ligand-receptor complexes.Results: Two new natural compounds ZINC000049872065 and ZINC000021992902 were found to bind to AKT1 in the ZINC database, showing a higher binding affinity. Also, they were predicted to have lower rodent carcinogenicity, Ames mutagenicity, developmental toxicity potential, and high tolerance to cytochrome P4502D6. Molecular dynamics simulation shows that ZINC000049872065 and ZINC000021992902 have more favorable potential energies with AKT1, which can exist stably in the natural environment.Conclusion: This study suggests that ZINC000049872065 and ZINC000021992902 are ideal potential inhibitors of AKT1 targeting. These compounds are safe drug candidates and have important implications for the design and improvement of C-MET target drugs.

scholarly journals Natural xanthone compounds as promising drug candidates against COVID-19 - An integrated molecular docking and dynamics simulation study

2021 ◽  
Author(s):  
Shravan Kumar Gunda ◽  
Hima Kumari P ◽  
Anuj Kumar ◽  
P B. Kavi Kishor ◽  
Anil Kumar S
Keyword(s):  
Molecular Docking ◽  
Antiviral Agents ◽  
Binding Energies ◽  
Dynamics Simulation ◽  
Lipinski’S Rule ◽  
Drug Candidates ◽  
Main Protease ◽  
Lipinski’S Rule Of Five ◽  
Dynamics Simulations ◽  
Potential Inhibitors

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease2019 (COVID-19). SARS-CoV-2 is known for its high pathogenicity and transmission due to thepresence of polybasic cleavage sites. No specific drug is available for the treatment. To identifythe potential inhibitors, we have performed molecular docking against the SARS-CoV-2 mainprotease (6Y84) with fifteen important natural xanthone compounds. The docking results showedall the compounds exhibited good binding energies and interactions with the main protease. Thevalidation of representative docking complexes through molecular dynamics simulations showedthat xanthones binds with a higher binding affinity and lower free energy than the standardligand with Brasixanthone C and Brasixanthone B on 50 ns. Natural xanthone compounds havealso passed the Absorption, Distribution, Metabolism, and Excretion (ADME) property criteriaas well as Lipinski’s rule of five. The present integrated molecular docking and dynamicssimulations study unveil the use of xanthones as potential antiviral agents against SARS-CoV-2.

Multicanonical Molecular Dynamics Simulation Study of the Liquid-Solid and Solid-Solid Transitions in Lennard-Jones Clusters

2011 ◽  
Author(s):  
Toshihiro Kaneko ◽  
Kenji Yasuoka ◽  
Ayori Mitsutake ◽  
Xiao Cheng Zeng
Keyword(s):  
Molecular Dynamics ◽  
Heat Capacity ◽  
Transition Temperature ◽  
Peak Position ◽  
Temperature Curve ◽  
Dynamics Simulation ◽  
Lennard Jones ◽  
Dynamics Simulations ◽  
First Time ◽  
Good Agreement

Multicanonical molecular dynamics simulations are applied, for the first time, to study the liquid-solid and solid-solid transitions in Lennard-Jones (LJ) clusters. The transition temperatures are estimated based on the peak position in the heat capacity versus temperature curve. For LJ31, LJ58 and LJ98, our results on the solid-solid transition temperature are in good agreement with previous ones. For LJ309, the predicted liquid-solid transition temperature is also in agreement with previous result.

scholarly journals Reactive molecular dynamics simulation of the high-temperature pyrolysis of 2,2′,2′′,4,4′,4′′,6,6′,6′′-nonanitro-1,1′:3′,1′′-terphenyl (NONA)

RSC Advances ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 5507-5515
Author(s):  
Liang Song ◽  
Feng-Qi Zhao ◽  
Si-Yu Xu ◽  
Xue-Hai Ju
Keyword(s):  
Molecular Dynamics ◽  
High Temperature ◽  
Molecular Dynamics Simulation ◽  
Molecular Dynamics Simulations ◽  
Dynamics Simulation ◽  
Reactive Molecular Dynamics ◽  
Ring Compounds ◽  
Fused Ring ◽  
Dynamics Simulations

The bimolecular and fused ring compounds are found in the high-temperature pyrolysis of NONA using ReaxFF molecular dynamics simulations.

Molecular Dynamics Simulation Study of Lecithin Inhibiting Hydrate-Dissociation

2017 ◽  
Vol 890 ◽  
pp. 252-259
Author(s):  
Le Wang ◽  
Guan Cheng Jiang ◽  
Xin Lin ◽  
Xian Min Zhang ◽  
Qi Hui Jiang
Keyword(s):  
Molecular Dynamics ◽  
Water Movement ◽  
Simulation Analysis ◽  
Mass Density ◽  
Dynamics Simulation ◽  
Dissociation Process ◽  
Hydrate Dissociation ◽  
Hydrocarbon Chains ◽  
Dynamics Simulations ◽  
Mass Density Profile

Molecular dynamics simulations are used to study the dissociation inhibiting mechanism of lecithin for structure I hydrates. Adsorption characteristics of lecithin and PVP (poly (N-vinylpyrrolidine)) on the hydrate surfaces were performed in the NVT ensemble at temperatures of 277K and the hydrate dissociation process were simulated in the NPT ensemble at same temperature. The results show that hydrate surfaces with lecithin is more stable than the ones with PVP for the lower potential energy. The conformation of lecithin changes constantly after the balanced state is reached while the PVP molecular dose not. Lecithin molecule has interaction with lecithin nearby and hydrocarbon-chains of lecithin molecules will form a network to prevent the diffusion of water and methane molecules, which will narrow the available space for hydrate methane and water movement. Compared with PVP-hydrate simulation, analysis results (snapshots and mass density profile) of the dissociation simulations show that lecithin-hydrate dissociates more slowly.

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