Prevention of SARS-CoV-2 Proliferation with a Novel and Potent Main Protease Inhibitor by Docking, ADMET, MM-PBSA, and Molecular Dynamics Simulation

2021 ◽  
pp. 2150014
Author(s):  
Akbar Noorbakhsh ◽  
Rafee Habib Askandar ◽  
Mohammad Shakib Alhagh ◽  
Chiako Farshadfar ◽  
Seyed Hamid Seyedi ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Drug Target ◽  
Md Simulation ◽  
Vital Role ◽  
Lung Damage ◽  
Dynamics Simulation ◽  
Reference Drug ◽  
Main Protease ◽  
Poisson Boltzmann ◽  
Adme Properties

COVID-19 is the last disease caused by SARS-CoV-2 associated with a severe immune response and lung damage. The main protease (Mpro) has a vital role in SARS-CoV-2 proliferation. Moreover, humans lack homologous Mpro, which makes the Mpro a suitable drug target for the development of SARS-CoV-2 drugs. The purchasable L5000 library (Selleckchem Inc) includes 99,040 compounds that were used for virtual screening. After molecular docking and ADME studies, we selected a compound (WAY-604395) with a potent binding affinity to the Mpro active site and acceptable ADME properties compared to the reference drug (nelfinavir). Molecular dynamics (MD) simulation outcomes have proved that the Mpro-WAY604395 complex possesses a considerable value of flexibility, stability, compactness and binding energy. Our Molecular Mechanics Poisson–Boltzmann Surface Area (MM-PBSA) calculation demonstrates that WAY-604395 is more potent ([Formula: see text]272.19[Formula: see text]kcal mol[Formula: see text]) in comparison with nelfinavir ([Formula: see text]173.39[Formula: see text]kcal[Formula: see text]mol[Formula: see text]) against SARS-CoV-2 Mpro. In conclusion, we suggest that WAY-604395 has the potential for the treatment of SARS-CoV-2 by inhibition of the Mpro.

The computational approach of designing novel SARS-CoV-2 Mpro inhibitors: combined QSAR, molecular docking, and molecular dynamics simulation techniques

2021 ◽  
Author(s):  
Jianbo Tong ◽  
Ding Luo ◽  
Haiyin Xu ◽  
Shuai Bian ◽  
Xing Zhang ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Life Cycle ◽  
Vital Role ◽  
Computational Approach ◽  
Dynamics Simulation ◽  
Highly Active ◽  
Simulation Techniques ◽  
Main Protease ◽  
Normal Expression

The normal expression of the main protease (Mpro) plays a vital role in the life cycle of the coronavirus. Highly active inhibitors could inhibit the normal circulation of the main...

Molecular docking, molecular dynamics simulation, and ADMET analysis of levamisole derivatives against the SARS-CoV-2 main protease (MPro)

Bioimpacts ◽  
2021 ◽  
Author(s):  
Khalil EL Khatabi ◽  
Ilham Aanouz ◽  
Marwa Alaqarbeh ◽  
Mohammed Aziz Ajana ◽  
Tahar Lakhlifi ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Md Simulation ◽  
Antiviral Agents ◽  
Dynamics Simulation ◽  
Main Protease ◽  
In Silico Admet ◽  
Wet Lab ◽  
The Stability ◽  
Drug Leads

Introduction: The new species of coronaviruses (CoVs), SARS-CoV-2, was reported as responsible for an outbreak of respiratory disease. Scientists and researchers are endeavoring to develop new approaches for the effective treatment against of the COVID-19 disease. There are no finally targeted antiviral agents able to inhibit the SARS-CoV-2 at present. Therefore, it is of interest to investigate the potential uses of levamisole derivatives, which are reported to be antiviral agents targeting the influenza virus. Methods: In the present study, 12 selected levamisole derivatives containing imidazo[2,1-b]thiazole were subjected to molecular docking in order to explore the binding mechanisms between these derivatives and the SARS-CoV-2 Mpro (PDB: 7BQY). The levamisole derivatives were evaluated for in silico ADMET properties for wet-lab applicability. Further, the stability of the best-docked complex was checked using molecular dynamics (MD) simulation at 20 ns. Results: Levamisole derivatives and especially molecule N°6 showed more promising docking results, presenting favorable binding interactions as well as better docking energy compared to chloroquine and mefloquine. The results of ADMET prediction and MD simulation support the potential of the molecule N°6 to be further developed as a novel inhibitor able to stop the newly emerged SARS-CoV-2. Conclusion: This research provided an effective first line in the rapid discovery of drug leads against the novel CoV (SARS-CoV-2).

scholarly journals Synthesis of Novel Halogenated Heterocyclic compounds and their uses as Target SARS-CoV-2 main Protease (Mpro) and Potential Anti-Covid-19

2021 ◽  
Author(s):  
Rafat Mohareb ◽  
Fahad M. Almutairi ◽  
Abdo A. Elfiky ◽  
Mahmoud A.A. Mahmoud ◽  
Wagnat W. Wardakhan ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Active Site ◽  
Drug Target ◽  
Heterocyclic Compounds ◽  
Dynamics Simulation ◽  
Binding Modes ◽  
Main Protease ◽  
Target Molecules ◽  
Protein Active Site ◽  
Virtual Drug Screening

Abstract Since the first appearance of the coronavirus disease-2019 (COVID-19) in Wuhan, China, in December 2019, it has been spreading globally with devastating ramifications. The lack of anti-COVID-19 treatment to date warrants urgent research into potential therapeutic targets. Virtual drug screening techniques enable the identification of novel compounds that are capable of targeting the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro). The latter plays a fundamental role in mediating viral replication and transcription, rendering it an attractive drug target. In this study, twenty six novel halogenated, heterocyclic compounds, which can inhibit Mpro, were tested by molecular docking combined with molecular dynamics simulation. Three compounds showed the highest binding affinity to the protein active site and their binding modes coincide with that of Nelfinavir. The binding of the halogenated compounds to Mpro may inhibit the replication and transcription of SARS-CoV-2 and, ultimately, stop the virallife cycle. In times of dire need for anti-COVID-19 treatment, this study lays the groundwork for further experimental research to investigate the efficacy and potential medical uses of these compounds to treat COVID-19. Novel compounds including fused thiophene, pyrimidine and pyran derivatives were tested against human RNA N7-MTase (hRNMT) and selected viral N7-MTases such as SARS-CoV nsp14 and Vaccinia D1-D12 complex to evaluate their specificity and their molecular modeling was also studied in the aim of producing anti covid-19 target molecules.

scholarly journals Molecular dynamics simulation of sI methane hydrate under compression and tension

2020 ◽  
Vol 18 (1) ◽  
pp. 69-76
Author(s):  
Qiang Wang ◽  
Qizhong Tang ◽  
Sen Tian
Keyword(s):  
Molecular Dynamics ◽  
Methane Hydrate ◽  
Fracture Process ◽  
Md Simulation ◽  
Maximum Stress ◽  
Dynamics Simulation ◽  
Tensile Fracture ◽  
Maximum Compressive Stress ◽  
Motion State ◽  
Stress States

AbstractMolecular dynamics (MD) analysis of methane hydrate is important for the application of methane hydrate technology. This study investigated the microstructure changes of sI methane hydrate and the laws of stress–strain evolution under the condition of compression and tension by using MD simulation. This study further explored the mechanical property and stability of sI methane hydrate under different stress states. Results showed that tensile and compressive failures produced an obvious size effect under a certain condition. At low temperature and high pressure, most of the clathrate hydrate maintained a stable structure in the tensile fracture process, during which only a small amount of unstable methane broke the structure, thereby, presenting a free-motion state. The methane hydrate cracked when the system reached the maximum stress in the loading process, in which the maximum compressive stress is larger than the tensile stress under the same experimental condition. This study provides a basis for understanding the microscopic stress characteristics of methane hydrate.

scholarly journals Identification of Anti-SARS-CoV-2 Compounds from Food Using QSAR-Based Virtual Screening, Molecular Docking, and Molecular Dynamics Simulation Analysis

2021 ◽  
Vol 14 (4) ◽  
pp. 357
Author(s):  
Magdi E. A. Zaki ◽  
Sami A. Al-Hussain ◽  
Vijay H. Masand ◽  
Siddhartha Akasapu ◽  
Sumit O. Bajaj ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Virtual Screening ◽  
Simulation Analysis ◽  
Qsar Model ◽  
Quantitative Structure Activity Relationship ◽  
Dynamics Simulation ◽  
Multilinear Regression ◽  
Qsar Analysis ◽  
Main Protease

Due to the genetic similarity between SARS-CoV-2 and SARS-CoV, the present work endeavored to derive a balanced Quantitative Structure−Activity Relationship (QSAR) model, molecular docking, and molecular dynamics (MD) simulation studies to identify novel molecules having inhibitory potential against the main protease (Mpro) of SARS-CoV-2. The QSAR analysis developed on multivariate GA–MLR (Genetic Algorithm–Multilinear Regression) model with acceptable statistical performance (R2 = 0.898, Q2loo = 0.859, etc.). QSAR analysis attributed the good correlation with different types of atoms like non-ring Carbons and Nitrogens, amide Nitrogen, sp2-hybridized Carbons, etc. Thus, the QSAR model has a good balance of qualitative and quantitative requirements (balanced QSAR model) and satisfies the Organisation for Economic Co-operation and Development (OECD) guidelines. After that, a QSAR-based virtual screening of 26,467 food compounds and 360 heterocyclic variants of molecule 1 (benzotriazole–indole hybrid molecule) helped to identify promising hits. Furthermore, the molecular docking and molecular dynamics (MD) simulations of Mpro with molecule 1 recognized the structural motifs with significant stability. Molecular docking and QSAR provided consensus and complementary results. The validated analyses are capable of optimizing a drug/lead candidate for better inhibitory activity against the main protease of SARS-CoV-2.

Molecular Dynamics Simulation of AFM-Based Nanomachining Processes

2011 ◽  
Author(s):  
Rapeepan Promyoo ◽  
Hazim El-Mounayri ◽  
Kody Varahramyan ◽  
Ashlie Martini
Keyword(s):  
Molecular Dynamics ◽  
Friction Coefficient ◽  
Md Simulation ◽  
Computational Models ◽  
Dynamics Simulation ◽  
Radius Of Curvature ◽  
Force Microscopy ◽  
Indentation Force ◽  
Atomic Force ◽  
Development And Validation

Recently, atomic force microscopy (AFM) has been widely used for nanomachining and fabrication of micro/ nanodevices. This paper describes the development and validation of computational models for AFM-based nanomachining (nanoindentation and nanoscratching). The Molecular Dynamics (MD) technique is used to model and simulate mechanical indentation and scratching at the nanoscale in the case of gold and silicon. The simulation allows for the prediction of indentation forces and the friction force at the interface between an indenter and a substrate. The effects of tip curvature and speed on indentation force and friction coefficient are investigated. The material deformation and indentation geometry are extracted based on the final locations of atoms, which are displaced by the rigid tool. In addition to modeling, an AFM was used to conduct actual indentation at the nanoscale, and provide measurements to validate the predictions from the MD simulation. The AFM provides resolution on nanometer (lateral) and angstrom (vertical) scales. A three-sided pyramid indenter (with a radius of curvature ∼ 50 nm) is raster scanned on top of the surface and in contact with it. It can be observed from the MD simulation results that the indentation force increases as the depth of indentation increases, but decreases as the scratching speed increases. On the other hand, the friction coefficient is found to be independent of scratching speed.

Sign in / Sign up

Export Citation Format

Share Document