Recent Advances in Protein−Ligand Interactions: Molecular Dynamics Simulations and Binding Free Energy
30 Nov 2013-Current Computer - Aided Drug Design (Curr Comput Aided Drug Des)-Vol. 9, Iss: 4, pp 518-531
TL;DR: In the present review, some facts related to protein-ligand complexes are highlighted, by starting with a survey of MD simulations and binding free energy calculations and ending with some successful implementations of these computational techniques.
Abstract: Computational techniques are one of the most emerging topics in structural and molecular biology. Molecular dynamics (MD) simulations are used not only to explore the conformational aspects of biological systems but also to have significant scope in protein-ligand interactions. Then the binding free energy calculations are readily applied to the simulated systems in order to predict the binding affinities. The thermodynamic properties are directly related to protein-ligand interactions which are dependent upon a few specific parameters. In the present review, we highlight some facts related to protein-ligand complexes, by starting with a survey of MD simulations and binding free energy calculations and ending with some successful implementations of these computational techniques.
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TL;DR: Marine natural compounds may be used as a potential inhibitor against SARS-CoV-2 for better management of COVID-19, a single-stranded RNA virus responsible for severe acute respiratory disease.
Abstract: Sever acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a single-stranded RNA (ssRNA) virus, responsible for severe acute respiratory disease (COVID-19). A large number of natural compounds ...
107 citations
Cites background from "Recent Advances in Protein−Ligand I..."
...Both, RMSD and RMSF stabilities are essential to infer good binding affinities (Doniach & Eastman, 1999; Dubey et al., 2013; Figure 6)....
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TL;DR: Molecular docking analysis revealed that a potential antiviral peptide EEAGGATAAQIEM (E-M) could interact with residues Thr190, Thr25, Thr26, Ala191, Leu50, Met165, Gln189, Glu166, His164, His41, Cys145, Gly143, and Asn119 of Mpro via 11 conventional hydrogen bonds and one alkyl interaction.
43 citations
TL;DR: It was observed that the phytochemicals exhibit a remarkable multipotency with the ability to modulate various human biological pathways especially pathways in cancer, and need further detailed in vivo experimental evaluation and clinical validation to implement them as potent therapeutic agents for combating SARS‐CoV‐2.
Abstract: The natural way forward: Molecular dynamics simulation analysis of phytochemicals from Indian medicinal plants as potential inhibitors of SARS-CoV-2 targets/bbrbr/bPrataKumar Parida 1#, Dipak Paul 1#, Debamitra Chakravorty 2*#/bp1 Noor Enzymes Private Limited, 37-B, Darga Road, Kolkata - 700 017, Indiap2 Novel Techsciences (OPC) Private Limited, 37-B, Darga Road, 1st Floor, Kolkata - 700 017, Indiap* Corresponding author:pDebamitra Chakravorty, PhD (Project Lead - Computational Biology)pNovel Techsciences (OPC) Private Limited, 37-B, Darga Road, 1st Floor, Kolkata - 700 017, IndiapE-mail: a href="mailto:dc@noveltechsciences com"dc@noveltechsciences com/ap#All the authors have contributed equally to the paper Abstract/bThe pandemic COVID-19 has become a global panic and health issue forcing our lives towards a compromised "new normal" Research is still ongoing to develoeffective antiviral drugs and vaccines against SARS-CoV-2 Thus, to address the current outbreak, development of natural inhibitors as a prophylactic measure is an attractive strategy due to their natural diversity and safety Phytochemicals that target viral entry (Spike glycoprotein) and replication (3CLPro) are lucrative in terms of both economy and health for the treatment of the deadly virus In this context, this work explored natural compounds from Indian medicinal plants as potential inhibitors for containing the spread SARS-CoV-2 The phytochemicals were rationally screened from 55 Indian medicinal plants in our previous work All atom 100 ns molecular dynamics simulations were performed using high performance computing for 8 toscoring rationally screened phytochemicals from iWithania somniferaand iAzadirachta indica /iand two repurposed drugs against the spike glycoprotein and the main protease of SARS-CoV-2 MMBSA, Principal component analysis and hydrogen bond occupancy were analysed to characterize protein–ligand interactions and to find the binding free energy Biological pathway enrichment analysis was also carried out to observe the therapeutic efficacy of these phytochemicals The results revealed that Withanolide R (-141 96 KJ/Mol) and 2,3-Dihydrowithaferin A (-87 60 KJ/Mol) were with the lowest relative free energy of binding for main protease and the spike proteins respectively It was also observed that the phytochemicals exhibit a remarkable multipotency with the ability to modulate various human biological pathways especially pathways in cancer Conclusively we suggest that these compounds need further detailed iin vivoexperimental evaluation and clinical validation for implementation as potent therapeutic agent for combating SARS-CoV-2
34 citations
17 Dec 2020
TL;DR: In this article, the main protease (Mprotease) of SARS-CoV-2 was found to be the most efficient inhibitor of Mpro both in silico and in vitro.
Abstract: The recent pandemic caused by SARS-CoV-2 has led the world to a standstill, causing a medical and economic crisis worldwide. This crisis has triggered an urgent need to discover a possible treatment strategy against this novel virus using already-approved drugs. The main protease (Mpro) of this virus plays a critical role in cleaving the translated polypeptides that makes it a potential drug target against COVID-19. Taking advantage of the recently discovered three-dimensional structure of Mpro, we screened approved drugs from the Drug Bank to find a possible inhibitor against Mpro using computational methods and further validating them with biochemical studies. The docking and molecular dynamics study revealed that DB04983 (denufosol) showed the best glide docking score, -11.884 kcal/mol, and MM-PBSA binding free energy, -10.96 kcal/mol. Cobicistat, cangrelor (previous computational studies in our lab), and denufosol (current study) were tested for the in vitro inhibitory effects on Mpro. The IC50 values of these drugs were ∼6.7 μM, 0.9 mM, and 1.3 mM, respectively, while the values of dissociation constants calculated using surface plasmon resonance were ∼2.1 μM, 0.7 mM, and 1.4 mM, respectively. We found that cobicistat is the most efficient inhibitor of Mpro both in silico and in vitro. In conclusion, cobicistat, which is already an FDA-approved drug being used against HIV, may serve as a good inhibitor against the main protease of SARS-CoV-2 that, in turn, can help in combating COVID-19, and these results can also form the basis for the rational structure-based drug design against COVID-19.
22 citations
TL;DR: It is argued that the sensitivity of the absolute ΔΔGelec calculated with PBE using different input parameters and definitions does not indicate PBE deficiency, rather this is what should be expected, and how the apparent sensitivity should be interpreted in terms of the underlying changes in several numerous and physical parameters.
Abstract: Macromolecular interactions are essential for understanding numerous biological processes and are typically characterized by the binding free energy. Important component of the binding free energy is the electrostatics, which is frequently modeled via the solutions of the Poisson-Boltzmann Equations (PBE). However, numerous works have shown that the electrostatic component (ΔΔGelec ) of binding free energy is very sensitive to the parameters used and modeling protocol. This prompted some researchers to question the robustness of PBE in predicting ΔΔGelec . We argue that the sensitivity of the absolute ΔΔGelec calculated with PBE using different input parameters and definitions does not indicate PBE deficiency, rather this is what should be expected. We show how the apparent sensitivity should be interpreted in terms of the underlying changes in several numerous and physical parameters. We demonstrate that PBE approach is robust within each considered force field (CHARMM-27, AMBER-94, and OPLS-AA) once the corresponding structures are energy minimized. This observation holds despite of using two different molecular surface definitions, pointing again that PBE delivers consistent results within particular force field. The fact that PBE delivered ΔΔGelec values may differ if calculated with different modeling protocols is not a deficiency of PBE, but natural results of the differences of the force field parameters and potential functions for energy minimization. In addition, while the absolute ΔΔGelec values calculated with different force field differ, their ordering remains practically the same allowing for consistent ranking despite of the force field used. © 2016 Wiley Periodicals, Inc.
20 citations