scholarly journals Computational Study of Scorpion Venom (Lychas Mucronatus) Activity as Antimicrobial Peptides (AMPs) to the SARS-CoV-2 Main Protease for the Future Coronavirus Disease (COVID-19) Inhibitors

Molekul ◽  
2021 ◽  
Vol 16 (2) ◽  
pp. 125
Author(s):  
Taufik Muhammad Fakih
Keyword(s):  
Antimicrobial Peptides ◽  
Computational Study ◽  
Binding Free Energy ◽  
Scorpion Venom ◽  
Computational Approach ◽  
Free Energy Calculations ◽  
World Health ◽  
Peptide Docking ◽  
Main Protease ◽  
Molecular Stability

The 2019 coronavirus pandemic disease (COVID-19) is still declared a global pandemic by the World Health Organization (WHO). Therefore, an effort that is considered effective in finding therapeutic agents is needed to prevent the spread of COVID-19 infection. One of the steps that can be chosen is by utilizing antimicrobial peptides (AMPs) from animal venom by targeting the specific receptor of SARS-CoV-2, namely the main protease (Mpro). Through this research, a computational approach will be conducted to predict antiviral activity, including protein-peptide docking using PatchDock algorithm, to identify, evaluate, and explore the affinity and molecular interactions of four types of antimicrobial peptides (AMPs), such as Mucroporin, Mucroporin-M1, Mucroporin-S1, and Mucroporin-S2 derived from scorpion venom (Lychas mucronatus) against main protease (Mpro) SARS-CoV-2. These results were then confirmed using protein-peptide interaction dynamics simulations for 50 ns using Gromacs 2016 to observe the molecular stability to the binding site of SARS-CoV-2 Mpro. Based on protein-peptide docking simulations, it was proven that the Mucroporin S-1 peptides have a good affinity against the active site area of SARS-CoV-2 Mpro, with an ACE score of −779.56 kJ/mol. Interestingly, Mucroporin-S1 was able to maintain the stability of its interactions based on the results of RMSD, RMSF, and MM/PBSA binding free energy calculations. The results of the computational approach predict that the Mucroporin-S1 peptide is expected to be useful for further research in the development of new antiviral-based AMPs for the COVID-19 infectious disease. 

scholarly journals Old Arsenal to Combat New Enemy: Repurposing of Commercially Available FDA Approved Drugs Against Main Protease of SARS-CoV2.

2020 ◽  
Author(s):  
Gagandeep Singh ◽  
vishal srivastava ◽  
Ritpratik Mishra ◽  
Gaurav Goel ◽  
Tapan Chaudhuri
Keyword(s):  
Drug Design ◽  
Binding Free Energy ◽  
Md Simulations ◽  
Docking Studies ◽  
Free Energy Calculations ◽  
World Health ◽  
Main Protease ◽  
Health Organization ◽  
Approved Drugs ◽  
Potential Inhibitors

<p> In lack of vaccination and therapeutic drugs, the ongoing COVID-19 pandemic affected millions of people, causing 1,018,957 deaths worldwide (World health organization; 1<sup>st</sup> October 2020). The conventional drug design pipeline for effective and safer drug development is a costly and time-intensive affair. It takes around ten years in general from identifying a clinical candidate to get the approvals for actual applications. An effective way to cut short drug design pipeline in such emergency cases could be the repurposing of already approved drugs against novel targets. Here in this work, we explored the structure-based drug screening approach to find potential inhibitors of SARS-CoV2 main protease (M<sup>pro</sup>) from the library of already FDA approved commercially available drugs. The site-specific and blind docking studies, in combination, suggest three potential inhibitors of M<sup>pro</sup>, Ergotamine (ZINC000052955754), Nilotinib (ZINC000006716957) and Naldemedine (ZINC000100378061). Molecular dynamics (MD) simulations and binding free energy calculations using the MMPBSA method further reinforced the efficiency of the screened M<sup>pro</sup> inhibitor candidates. The work yields enough evidence to conduct rigorous experimental validation of these drugs before utilizing them for the therapeutic management of SARS-CoV2 infection.</p>

scholarly journals Old Arsenal to Combat New Enemy: Repurposing of Commercially Available FDA Approved Drugs Against Main Protease of SARS-CoV2.

2020 ◽  
Author(s):  
Gagandeep Singh ◽  
vishal srivastava ◽  
Ritpratik Mishra ◽  
Gaurav Goel ◽  
Tapan Chaudhuri
Keyword(s):  
Drug Design ◽  
Binding Free Energy ◽  
Md Simulations ◽  
Docking Studies ◽  
Free Energy Calculations ◽  
World Health ◽  
Main Protease ◽  
Health Organization ◽  
Approved Drugs ◽  
Potential Inhibitors

<p> In lack of vaccination and therapeutic drugs, the ongoing COVID-19 pandemic affected millions of people, causing 1,018,957 deaths worldwide (World health organization; 1<sup>st</sup> October 2020). The conventional drug design pipeline for effective and safer drug development is a costly and time-intensive affair. It takes around ten years in general from identifying a clinical candidate to get the approvals for actual applications. An effective way to cut short drug design pipeline in such emergency cases could be the repurposing of already approved drugs against novel targets. Here in this work, we explored the structure-based drug screening approach to find potential inhibitors of SARS-CoV2 main protease (M<sup>pro</sup>) from the library of already FDA approved commercially available drugs. The site-specific and blind docking studies, in combination, suggest three potential inhibitors of M<sup>pro</sup>, Ergotamine (ZINC000052955754), Nilotinib (ZINC000006716957) and Naldemedine (ZINC000100378061). Molecular dynamics (MD) simulations and binding free energy calculations using the MMPBSA method further reinforced the efficiency of the screened M<sup>pro</sup> inhibitor candidates. The work yields enough evidence to conduct rigorous experimental validation of these drugs before utilizing them for the therapeutic management of SARS-CoV2 infection.</p>

scholarly journals Identification of the Potential Hits for Hindering Interaction of SARS-CoV-2 Main Protease (M pro ) from the Pool of Antiviral Phytochemicals utilizing Molecular Docking and Molecular Dynamics (MD) Simulations

2021 ◽  
Author(s):  
Chirag N. Patel ◽  
Dharmesh G. Jaiswal ◽  
Siddhi P. Jani ◽  
Naman Mangukia ◽  
Robin M. Parmar ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Docking ◽  
Virus Assembly ◽  
Binding Free Energy ◽  
Natural Compounds ◽  
Free Energy Calculations ◽  
Host Protein ◽  
Dynamic Simulations ◽  
Main Protease

Abstract The novel SARS-CoV-2 is an etiological factor that triggers Coronavirus disease in 2019 (COVID-19) and tends to be an imminent occurrence of a pandemic. Out of all recognized solved complexes linked to SARS-CoV, Main protease (Mpro) is considered a desirable antiviral phytochemical that play a crucial role in virus assembly and possibly non-interactive capacity to adhere to any viral host protein. In this research, SARS-CoV-2 MPro was chosen as a focus for the detection of possible inhibitors using a variety of different analytical methods such as molecular docking, ADMET analysis, dynamic simulations and binding free energy measurements. Virtual screening of known natural compounds recognized Withanoside V, Withanoside VI, Racemoside B, Racemoside A and Shatavarin IX as future inhibitors of SARS-CoV-2 MPro with stronger energy binding. Also, simulations of molecular dynamics for a 100 ns time scale showed that much of the main SARS-CoV-2 MPro interactions had been maintained in the simulation routes. Binding free energy calculations using the MM/PBSA method ranked the top five possible natural compounds that can act as effective SARS-CoV-2 MPro inhibitors.

scholarly journals Identification of antiviral phytochemicals as a potential SARS-CoV-2 main protease (Mpro) inhibitor using docking and molecular dynamics simulations

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Chirag N. Patel ◽  
Siddhi P. Jani ◽  
Dharmesh G. Jaiswal ◽  
Sivakumar Prasanth Kumar ◽  
Naman Mangukia ◽  
...  
Keyword(s):  
Free Energy ◽  
Binding Free Energy ◽  
Natural Compounds ◽  
Free Energy Calculations ◽  
Public Health Care ◽  
Dynamic Simulations ◽  
Energy Calculations ◽  
Main Protease ◽  
Binding Free Energy Calculations ◽  
Dynamics Simulations

AbstractNovel SARS-CoV-2, an etiological factor of Coronavirus disease 2019 (COVID-19), poses a great challenge to the public health care system. Among other druggable targets of SARS-Cov-2, the main protease (Mpro) is regarded as a prominent enzyme target for drug developments owing to its crucial role in virus replication and transcription. We pursued a computational investigation to identify Mpro inhibitors from a compiled library of natural compounds with proven antiviral activities using a hierarchical workflow of molecular docking, ADMET assessment, dynamic simulations and binding free-energy calculations. Five natural compounds, Withanosides V and VI, Racemosides A and B, and Shatavarin IX, obtained better binding affinity and attained stable interactions with Mpro key pocket residues. These intermolecular key interactions were also retained profoundly in the simulation trajectory of 100 ns time scale indicating tight receptor binding. Free energy calculations prioritized Withanosides V and VI as the top candidates that can act as effective SARS-CoV-2 Mpro inhibitors.

scholarly journals Nelfinavir was predicted to be a potential inhibitor of 2019-nCov main protease by an integrative approach combining homology modelling, molecular docking and binding free energy calculation

2020 ◽  
Author(s):  
Zhijian Xu ◽  
Cheng Peng ◽  
Yulong Shi ◽  
Zhengdan Zhu ◽  
Kaijie Mu ◽  
...  
Keyword(s):  
Free Energy ◽  
Binding Free Energy ◽  
Homology Modelling ◽  
Binding Mode ◽  
Free Energy Calculations ◽  
Integrative Approach ◽  
Energy Calculation ◽  
Potential Inhibitor ◽  
Small Molecule Drugs ◽  
Main Protease

Abstract2019-nCov has caused more than 80 deaths as of 27 January 2020 in China, and infection cases have been reported in more than 10 countries. However, there is no approved drug to treat the disease. 2019-nCov Mpro is a potential drug target to combat the virus. We built homology models based on SARS Mpro structures, and docked 1903 small molecule drugs to the models. Based on the docking score and the 3D similarity of the binding mode to the known Mpro ligands, 4 drugs were selected for binding free energy calculations. Both MM/GBSA and SIE methods voted for nelfinavir, with the binding free energy of −24.69±0.52 kcal/mol and −9.42±0.04 kcal/mol, respectively. Therefore, we suggested that nelfinavir might be a potential inhibitor against 2019-nCov Mpro.

Computational Investigation of Increased Virulence and Pathogenesis of SARS-CoV-2 Lineage B.1.1.7

2021 ◽  
Author(s):  
N. Arul Murugan ◽  
Prashanth S. Javali ◽  
Chitra Jeyaraj Pandian ◽  
Muhammad Akhtar Ali ◽  
Vaibhav Srivastava ◽  
...  
Keyword(s):  
Density Functional ◽  
Binding Free Energy ◽  
Intermolecular Hydrogen Bond ◽  
Decomposition Analysis ◽  
Free Energy Calculations ◽  
Spike Protein ◽  
World Health ◽  
Free Energies ◽  
Wild Type ◽  
Host Immune Responses

AbstractNew variants of SARS-CoV-2 are being reported worldwide. More specifically, the variants reported in South Africa (501Y.V2) and United Kingdom (B.1.1.7) were found to be more contagious than the wild type. There are also speculations that the variants might evade the host immune responses induced by currently available vaccines and develop resistance to drugs under consideration. The first step of viral infection in COVID-19, occurs through the interaction of receptor binding domain (RBD) of the spike protein with peptidase domain of the human ACE-2 (hACE-2) receptor. So, possibly the mutations in the RBD domain of spike protein in the new variants could modulate the protein-protein interaction with hACE-2 receptor leading to the increased virulence. In this study, we aim to get molecular level understanding into the mechanism behind the increased infection rate due to such mutations in these variants. We have computationally studied the interaction of the spike protein in both wild-type and B.1.1.7 variant with hACE-2 receptor using combined molecular dynamics and binding free energy calculations using molecular mechanics-Generalized Born surface area (MM-GBSA) approach. The binding free energies computed using configurations from minimization run and low temperature simulation show that mutant variant of spike protein has increased binding affinity for hACE-2 receptor (i.e. ΔΔG(N501Y,A570D) is in the range −20.4 to −21.4 kcal/mol)The residue-wise decomposition analysis and intermolecular hydrogen bond analysis evidenced that the N501Y mutation has increased interaction between RBD of spike protein with ACE-2 receptor. We have also carried out calculations using density functional theory and the results evidenced the increased interaction between three pairs of residues (TYR449 (spike)-ASP38 (ACE-2), TYR453-HIE34 and TYR501-LYS353) in the variant that could be attributed to its increased virulence. The free energies of wild-type and mutant variants of the spike protein computed from MM-GBSA approach suggests that latter variant is stable by about −10.4 kcal/mol when compared to wild type suggesting that it will be retained in the evolution due to increased stability. We demonstrate that with the use of the state-of-the art of computational approaches, we can in advance predict the more virulent nature of variants of SARS-CoV-2 and alert the world health-care system.

scholarly journals Potential Ebola drug targets – filling the gap: a critical step forward towards the design and discovery of potential drugs

Biologia ◽  
2017 ◽  
Vol 72 (1) ◽  
pp. 1-13 ◽  
Author(s):  
Marissa Balmith ◽  
Mahmoud E.S. Soliman
Keyword(s):  
Binding Site ◽  
Active Site ◽  
Active Sites ◽  
Binding Free Energy ◽  
Three Dimensional ◽  
Computational Prediction ◽  
Homology Model ◽  
Free Energy Calculations ◽  
Biologically Active ◽  
World Health

AbstractAmong the classified neglected infectious diseases, the Ebola virus (EboV) remains a challenging epidemic. This deadly virus has been reported as a category A bioweapon organism by the World Health Organization due to the serious threat it poses. To date, Ebola drug discovery proves challenging. Proteins need to be targeted at the relevant biologically active site for drug or inhibitor binding to be effective. Due to insufficient experimental data to confirm the biologically active binding site for novel protein targets, researchers often rely on computational prediction methods to identify binding sites. Many computational studies have attempted to identify the biological active site for EboV proteins, however, the methods employed are not sufficiently validated. This has prompted us to provide a comprehensive molecular understanding of the various targets of the EboV, including three-dimensional structures, active site identification and further validation. Herein we report the account of a three-dimensional homology model of the unresolved EboV RNA-dependent RNA polymerase (RdRp), as well as a comprehensive analysis of the binding site residues of all proteins of the EboV. Docking-aided active site determination was carried out to identify possible active sites on the homology model of RdRp. Binding free energy calculations revealed subtle differences in the binding at each site. These results can also provide some potential clues for further design of novel inhibitors to treat this killer virus and is a critical cornerstone of research into the EboV.

Covalent and non-covalent binding free energy calculations for peptidomimetic inhibitors of SARS-CoV-2 main protease

2021 ◽  
Author(s):  
Ernest Awoonor-Williams ◽  
Abd Al-Aziz A. Abu-Saleh
Keyword(s):  
Free Energy ◽  
Binding Free Energy ◽  
Covalent Binding ◽  
Free Energy Calculations ◽  
Total Binding Energy ◽  
Energy Calculations ◽  
Main Protease ◽  
Covalent Inhibitors ◽  
Binding Free Energy Calculations ◽  
Absolute Binding Free Energy

This work employs rigorous absolute binding free energy calculations and QM/MM methods to calculate the total binding energy of two recently crystallized peptidomimetic covalent inhibitors of the SARS-CoV-2 Mpro target.

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