Insights into structural dynamics of allosteric binding sites in HCV RNA-dependent RNA polymerase

Mittal, Lovika; Kumari, Anita; Suri, Charu; Bhattacharya, Sankar; Asthana, Shailendra

doi:10.1080/07391102.2019.1614480

Cited by 24 publications

(42 citation statements)

References 34 publications

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“…The grid was generated using the centroid of N3 by using the Receptor Grid Generation panel in Glide. Docking studies were carried out using the VS Workflow (VSW) of Glide Schrodinger Suite (Friesner et al, 2006;Mittal et al, 2020).The ligands chosen from the database were passed through three stages of the screening workflow starting from high-throughput screening (50% filtered), followed by standard precision (30%) and finally extra precision (10%) stages. The final poses were processed using the Prime MM-GBSA panel at the end (Schrodinger suite, LLC, New York, NY, 2016-3) ( Supplementary Figure 1).…”

Section: Virtual Screening Of Virtual Libraries On M Promentioning

confidence: 99%

“…where the difference in the minimized energies between ligand and protein complexes is denoted by DE MM . DG solv is the difference in the GBSA solvation energy of the complexes and sum of solvation energies for the protein and ligand, whereas the differences in surface area energy of the complex and sum of that in protein and ligand (Kellici et al, 2019;Mittal et al, 2020).…”

Section: Virtual Screening Of Virtual Libraries On M Promentioning

confidence: 99%

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Identification of potential molecules against COVID-19 main protease through structure-guided virtual screening approach

Mittal

Kumari

Srivastava

et al. 2020

Journal of Biomolecular Structure and Dynamics

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160

102

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The pandemic caused by novel coronavirus disease 2019 infecting millions of populations worldwide and counting, has demanded quick and potential therapeutic strategies. Current approved drugs or molecules under clinical trials can be a good pool for repurposing through in-silico techniques to quickly identify promising drug candidates. The structural information of recently released crystal structures of main protease (M pro ) in APO and complex with inhibitors, N3, and 13b molecules was utilized to explore the binding site architecture through Molecular dynamics (MD) simulations. The stable state of M pro was used to conduct extensive virtual screening of the aforementioned drug pool. Considering the recent success of HIV protease molecules, we also used anti-protease molecules for drug repurposing purposes. The identified top hits were further evaluated through MD simulations followed by the binding free energy calculations using MM-GBSA. Interestingly, in our screening, several promising drugs stand out as potential inhibitors of M pro . However, based on control (N3 and 13b), we have identified six potential molecules, Leupeptin Hemisulphate, Pepstatin A, Nelfinavir, Birinapant, Lypression and Octreotide which have shown the reasonably significant MM-GBSA score. Further insight shows that the molecules form stable interactions with hot-spot residues, that are mainly conserved and can be targeted for structure-and pharmacophore-based designing. The pharmacokinetic annotations and therapeutic importance have suggested that these molecules possess drug-like properties and pave their way for in-vitro studies. ARTICLE HISTORY

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Section: Virtual Screening Of Virtual Libraries On M Promentioning

confidence: 99%

Section: Virtual Screening Of Virtual Libraries On M Promentioning

confidence: 99%

Identification of potential molecules against COVID-19 main protease through structure-guided virtual screening approach

Mittal

Kumari

Srivastava

et al. 2020

Journal of Biomolecular Structure and Dynamics

Self Cite

160

102

View full text Add to dashboard Cite

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“…Docking Studies: We performed docking studies using two different strategies, first we excluded B, C and D chains and used only "A" chain for docking and in the second iteration we used all 4 chains which is the complete enzyme complex. Recent reports indicate that nsp12(chain A) has low template binding and processivity rate by itself, for efficient binding and activity the whole enzyme complex with chain A, B, C & D are required 7,8 . Hence, we also performed docking studies with the whole enzyme complex comprising of nsp12, nsp7 and nsp8.…”

Section: Methodsmentioning

confidence: 99%

Anti Hepatitis C Viral Drugs Remdesivir and Uprifosbuvir Derivatives Are Better Inhibitors of SARS Cov2 RNA-Dependent RNA Polymerase Determined by Docking Studies. .

Gudipati

Biswas²,

goyal³

2020

Preprint

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SARS Cov2 RNA-dependent RNA polymerase (RdRp) is an enzyme that catalyzes the synthesis and replication of viral RNA from an RNA template. Our starting model for this study was (SARS-Cov-2) cryo-EM structure published recently (pdb ID 6m71). We have used docking studies to find a better inhibitor for the enzyme that can be used in the treatment of SARS-CoV2 infections. Recently, several inhibitors like Sofosbuvir, Ribavirin, and Remdesivir has been reported as strong inhibitors of this enzyme. Our results show an analogue of Remdesivir such as CHEMBL3120791 and analogue of Uprifosbuvir SCHEMBL20762917, SCHEMBL20733228 as better inhibitors than previously reported inhibitors of RNAdependent RNA polymerase. Using Autodock Vina and Pyrx software for virtual screening of ligands, we found four higher efficiency compounds CHEMBL3120791, SCHEMBL20762917 SCHEMBL20733228, and Uprifosbuvir. The binding constant of these ligands were -9.5 (Kcal/mol), -8.3 (Kcal/mol), -8.3 (Kcal/mol), -8.6 (Kcal/mol), respectively when tested on SARS-COV-2 nsp12. Active site interactions with the potential drug molecule are with residues Lys47, Tyr129, Ser784, His133, Ser709 for CHEMBL3120791, SCHEMBL20762917 SCHEMBL20733228. These molecules can be used in the future drug development process in the treatment of SARS-Cov2 infection. The molecules reported here are already under clinical trial for the treatment of HCV (Hepatitis C Virus) infections, which is similar to SARS Cov2, as both are positive-sense RNA Viruses.

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“…The grid was generated using the centroid of bound inhibitor by using the Receptor Grid Generation panel in Glide. Docking studies were carried out using the Virtual Screening Workflow (VSW) of Glide Schrodinger Suite (Friesner et al, 2006;Mittal et al, 2020). The ligands chosen from the database were passed through three stages of the screening workflow starting from highthroughput screening (50% filtered), followed by standard precision (30%) and finally extra precision (10%) stages.…”

Section: Virtual Screening Of Virtual Libraries On M Promentioning

confidence: 99%

Identification of Potential Molecules Against COVID-19 Main Protease Through Structure-Guided Virtual Screening Approach

Mittal¹,

Kumari²,

Srivastava³

et al. 2020

Preprint

Self Cite

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In this work, computer-aided drug design method has been implemented to quickly identify promising drug repurposing candidates against COVID-19 main protease (Mpro) . The world is facing an epidemic and in absence of vaccine or any effective treatment, it has created a sense of urgency for novel drug discovery approaches. We have made an immediate effort by performing virtual screening of clinically approved drugs or molecules under clinical trials against COVID-19 Mpro to identify potential drug molecules. With given knowledge of this system, N3 and 13B compounds have shown inhibitory effect against COVID-19 Mpro. Both the compounds were considered as control to filter out the screened molecules. Overall, we have identified six potential compounds, Leupeptin Hemisulphate, Pepstatin A, Nelfinavir , Birinapant, Lypression and Octeotide which have shown the docking energy > -8.0 kcal/mol and MMGBSA > -68.0 kcal/mol. The binding pattern of these compounds suggests that they interacted with key hot-spot residues. Also, their pharmacokinetic annotations and therapeutic importance have indicated that they possess drug-like properties and could pave their way for in-vitro studies. The findings of this work will be significant for structure and pharmacophore-based designing.

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Insights into structural dynamics of allosteric binding sites in HCV RNA-dependent RNA polymerase

Cited by 24 publications

References 34 publications

Identification of potential molecules against COVID-19 main protease through structure-guided virtual screening approach

Identification of potential molecules against COVID-19 main protease through structure-guided virtual screening approach

Anti Hepatitis C Viral Drugs Remdesivir and Uprifosbuvir Derivatives Are Better Inhibitors of SARS Cov2 RNA-Dependent RNA Polymerase Determined by Docking Studies. .

Identification of Potential Molecules Against COVID-19 Main Protease Through Structure-Guided Virtual Screening Approach

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