Structural insight to hydroxychloroquine-3C-like proteinase complexation from SARS-CoV-2: inhibitor modelling study through molecular docking and MD-simulation study

Mukherjee, Somenath; Dasgupta, Subrata; Adhikary, Tapasendra; Adhikari, Utpal; Panja, Sujit S.

doi:10.1080/07391102.2020.1804458

Cited by 25 publications

(10 citation statements)

References 102 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There are a few spaces of life sciences where the approaches of docking and MD reproductions have been of an incredible use [32][33][34]. Comparable examinations utilizing docking and MD reproductions are likewise performed for accessing the potency of hydroxychloroquine with various targets of SARS-CoV2 [35].…”

Section: Admet Analysismentioning

confidence: 99%

Identifying structural–functional analogue of GRL0617, the only well-established inhibitor for papain-like protease (PLpro) of SARS-CoV2 from the pool of fungal metabolites using docking and molecular dynamics simulation

et al. 2021

View full text Add to dashboard Cite

The non-structural protein (nsp)-3 of SARS-CoV2 coronavirus is sought to be an essential target protein which is also named as papain-like protease (PLpro). This protease cleaves the viral polyprotein, but importantly in human host it also removes ubiquitin-like interferon-stimulated gene 15 protein (ISG15) from interferon responsive factor 3 (IRF3) protein which ultimately downregulates the production of type I interferon leading to weakening of immune response. GRL0617 is the most potent known inhibitor for PLpro that was initially developed for SARS outbreak of 2003. The PLpro of SARS-CoV and CoV2 share 83% sequence identity but interestingly have several identical conserved amino acids that suggests GRL0617 to be an effective inhibitor for PLpro of SARS-CoV2. GRL0617 is a naphthalene-based molecule and interacts with Tyr268 of SARS-CoV2-PLpro (and Tyr269 of SARS-CoV-PLpro). To identify PLpro inhibitors, we prepared a library of secondary metabolites from fungi with aromatic nature and docked them with PLpro of SARS-CoV and SARS-CoV2. We found six hits which interacts with Tyr268 of SARS-CoV2-PLpro (and Tyr269 of SARS-CoV-PLpro). More surprisingly the top hit, Fonsecin, has naphthalene moiety in its structure, which recruits Tyr268 of SARS-CoV2-PLpro (and Tyr269 of SARS-CoV-PLpro) and has binding energy at par with control (GRL0617). Molecular dynamics (MD) simulation showed Fonsecin to interact with Tyr268 of SARS-CoV2-PLpro more efficiently than control (GRL0617) and interacting with a greater number of amino acids in the binding cleft of PLpro. Graphic abstract

show abstract

Section: Admet Analysismentioning

confidence: 99%

Identifying structural–functional analogue of GRL0617, the only well-established inhibitor for papain-like protease (PLpro) of SARS-CoV2 from the pool of fungal metabolites using docking and molecular dynamics simulation

et al. 2021

View full text Add to dashboard Cite

show abstract

“…There are a few spaces of life sciences where the approaches of docking and MD reproductions have been of an incredible use [ [51] , [52] , [53] ]. Comparable examinations utilizing docking and MD reproductions are likewise performed for accessing the potency of hydroxychloroquine with various targets of SARS-CoV-2 [ 54 ].…”

Section: Discussionmentioning

confidence: 99%

Pinpointing the potential hits for hindering interaction of SARS-CoV-2 S-protein with ACE2 from the pool of antiviral phytochemicals utilizing molecular docking and molecular dynamics (MD) simulations

Patel

Goswami

Jaiswal

et al. 2021

Journal of Molecular Graphics and Modelling

View full text Add to dashboard Cite

SARS-CoV-2, the viral particle, is responsible for triggering the 2019 Coronavirus disease outbreak (COVID-19). To tackle this situation, a number of strategies are being devised to either create an antidote, a vaccine, or agents capable of preventing its infection. To enable research on these strategies, numerous target proteins are identified where Spike (S) protein is presumed to be of immense potential. S-protein interacts with human angiotensin-converting-enzyme-2 (ACE2) for cell entry. The key region of S-protein that interacts with ACE2 is a portion of it designated as a receptor-binding domain (RBD), following whereby the viral membrane fuses with the alveolar membrane to enter the human cell. The proposition is to recognise molecules from the bundle of phytochemicals of medicinal plants known to possess antiviral potentials as a lead that could interact and mask RBD, rendering them unavailable to form ACE2 interactions. Such a molecule is called the 'S-protein blocker’. A total of 110 phytochemicals from Withania somnifera , Asparagus racemosus, Zinziber officinalis , Allium sativum , Curcuma longa and Adhatoda vasica were used in the study, of which Racemoside A, Ashwagandhanolide, Withanoside VI, Withanoside IV and Racemoside C were identified as top five hits using molecular docking. Further, essential Pharmacophore features and their ADMET profiles of these compounds were studied following to which the best three hits were analyzed for their interaction with RBD using Molecular Dynamics (MD) simulation. Binding free energy calculations were performed using MM/GBSA, proving these phytochemicals can serve as S-protein blocker.

show abstract

“…All the above-mentioned studies have been carried out in silico using molecular dynamic simulation and docking studies. In addition, these approaches have also been utilized for potency assessment of hydroxychloroquine against various potential targets of SARS-CoV2 [ 39 ]. In all of these studies the rationale is very basic that if any of these drugs can meddle with the viral proteins and targets, then they can hinder the normal life cycle of the virus [ 40 , 41 ].…”

Section: Discussionmentioning

confidence: 99%

Repurposing the antibacterial drugs for inhibition of SARS-CoV2-PLpro using molecular docking, MD simulation and binding energy calculation

et al. 2021

View full text Add to dashboard Cite

Graphic abstract Papain-like protease (nsp-3; non-structural protein) of novel corona virus is an ideal target for developing drugs as it plays multiple important functions for viral growth and replication. For instance, role of nsp-3 has been recognized in cleavage of viral polyprotein; furthermore, in infected host it weakens the immune system via downregulating the production of type I interferon. This downregulation is promoted by removal of ubiquitin-like interferon-stimulated gene 15 protein (ISG15) from interferon-responsive factor 3 (IRF3) protein. Among known inhibitors of SARS-CoV-PLpro GRL0617 is by far the most effective inhibitor. As PLpro of SARS-CoV2 is having more than 80% similarity with SARS-CoV-PLpro, GRL0617 is reported to be effective even against SARS-CoV2. Owing to this similarity, certain key amino acids remain the same/conserved in both proteins. Among conserved amino acids Tyr268 for SARS-CoV2 and Tyr269 for SARS-CoV produce important hydrophobic interactions with aromatic rings of GRL0617. Here, in this study antibacterial compounds were collected from ZINC database, and they were filtered to select compounds that are having similar structural features as GRL0617. This filtered library of compound was then docked with SARS-CoV and CoV2-PLpro. Five hits were noted that were able to interact with Tyr268 (SARS-CoV2) and Tyr269 (SARS-CoV). Further, best hit 2-(2-((benzofuran-2-carboxamido)methyl)-5-methoxy-1H-indol-1-yl)acetic acid (ZINC44459905) was studied using molecular dynamic simulation where stability of protein–ligand complex as well as stability of produced interactions was noted.

show abstract

Structural insight to hydroxychloroquine-3C-like proteinase complexation from SARS-CoV-2: inhibitor modelling study through molecular docking and MD-simulation study

Cited by 25 publications

References 102 publications

Identifying structural–functional analogue of GRL0617, the only well-established inhibitor for papain-like protease (PLpro) of SARS-CoV2 from the pool of fungal metabolites using docking and molecular dynamics simulation

Identifying structural–functional analogue of GRL0617, the only well-established inhibitor for papain-like protease (PLpro) of SARS-CoV2 from the pool of fungal metabolites using docking and molecular dynamics simulation

Pinpointing the potential hits for hindering interaction of SARS-CoV-2 S-protein with ACE2 from the pool of antiviral phytochemicals utilizing molecular docking and molecular dynamics (MD) simulations

Repurposing the antibacterial drugs for inhibition of SARS-CoV2-PLpro using molecular docking, MD simulation and binding energy calculation

Contact Info

Product

Resources

About