Identifying the natural polyphenol catechin as a multi-targeted agent against SARS-CoV-2 for the plausible therapy of COVID-19: an integrated computational approach

Mishra, Chandra Bhushan; Pandey, Preeti; Sharma, Ravi Datta; Malik, Md. Zubbair; Mongre, Raj Kumar; Lynn, Andrew M.; Prasad, Rajendra; Jeon, Raok; Prakash, Amresh

doi:10.1093/bib/bbaa378

Cited by 80 publications

(58 citation statements)

References 84 publications

(81 reference statements)

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“…High frequency of mutation drives viral evolution as well as genome variability and hence enabling viruses to evade the immunity of host and soon develop drug resistance. RNA viruses including SARS-CoV-2 have potential ability to accumulate genomic mutations through an error- prone viral enzyme reverse transcriptase and better adapt inside the host that further creates hurdles in designing antiviral therapeutics against RNA viruses (Mishra et al 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Identification and characterization of mutations in the SARS-CoV-2 RNA-dependent RNA polymerase as a promising antiviral therapeutic target

Yashvardhini

Jha²,

Bhattacharya

2021

Arch Microbiol

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The causative agent of COVID-19 is a novel betacoronavirus or severe acute respiratory syndrome coronavirus (SARS-CoV-2), which has emerged as a pandemic of global concern. Considering its rapid transmission, WHO has declared public health emergency on 11th March 2020 worldwide. SARS-CoV-2 is a genetically diverse positive sense RNA virus that typically exhibit high rates of mutation than DNA viruses. Higher rates of mutation bring higher genomic variability which may lead to viral evolution and enabling viruses to evade the pre-existing immunity of host and quickly acquire drug resistance properties. The objective of our study was to compare the SARS-CoV-2 RdRp sequences of Indian SARS-CoV-2 isolates with those of Wuhan type virus. A total of 384 point mutations were detected from 488 sequence of the RdRp protein of Indian SARS-CoV-2 genome, out of which seven were used for subsequent study. Furthermore, prediction of secondary structure, protein modeling and its dynamics were performed which revealed that seven mutations (R118C, T148I, Y149C, E802A, Q822H, V880I and D893Y) significantly altered the stability and flexibility of RdRp protein. Present study was therefore, undertaken to analyze the variations occurring in RdRp due to multiple mutations leading to the alterations in the structure and function of RNA-dependent RNA polymerase which is essential for the replication /transcription of this virus and hence can be utilized as a promising therapeutic target to curb SARS-CoV-2 infections. Supplementary Information The online version contains supplementary material available at 10.1007/s00203-021-02527-9.

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Section: Discussionmentioning

confidence: 99%

Identification and characterization of mutations in the SARS-CoV-2 RNA-dependent RNA polymerase as a promising antiviral therapeutic target

Yashvardhini

Jha²,

Bhattacharya

2021

Arch Microbiol

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“…The rapidly emerging plethora of computational studies examined SARS-CoV-2-RBD interactions with ACE2 enzyme using the recent crystal structures providing insights into the key determinants of the binding affinity and selectivity. A comprehensive computational approach to identify the multi-targeted drug molecules against the SARS-CoV-2 proteins was recently discussed that synergistically combined MD simulations, free energy landscape analysis and molecular mechanics-Poisson-Boltzmann Surface Area (MM-PBSA) analysis (Mishra et al, 2021). Combined with structural insights this study identified catechin as a novel multi-targeted agent targeting SARS-CoV-2 proteins.…”

Section: Introductionmentioning

confidence: 99%

Computational analysis of protein stability and allosteric interaction networks in distinct conformational forms of the SARS-CoV-2 spike D614G mutant: reconciling functional mechanisms through allosteric model of spike regulation

Verkhivker

Agajanian

Öztaş

et al. 2021

Journal of Biomolecular Structure and Dynamics

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In this study, we used an integrative computational approach to examine molecular mechanisms underlying functional effects of the D614G mutation by exploring atomistic modeling of the SARS-CoV-2 spike proteins as allosteric regulatory machines. We combined coarse-grained simulations, protein stability and dynamic fluctuation communication analysis with network-based community analysis to examine structures of the native and mutant SARS-CoV-2 spike proteins in different functional states. Through distance fluctuations communication analysis, we probed stability and allosteric communication propensities of protein residues in the native and mutant SARS-CoV-2 spike proteins, providing evidence that the D614G mutation can enhance long-range signaling of the allosteric spike engine. By combining functional dynamics analysis and ensemble-based alanine scanning of the SARS-CoV-2 spike proteins we found that the D614G mutation can improve stability of the spike protein in both closed and open forms, but shifting thermodynamic preferences towards the open mutant form. Our results revealed that the D614G mutation can promote the increased number of stable communities and allosteric hub centers in the open form by reorganizing and enhancing the stability of the S1-S2 inter-domain interactions and restricting mobility of the S1 regions. This study provides atomistic-based view of allosteric communications in the SARS-CoV-2 spike proteins, suggesting that the D614G mutation can exert its primary effect through allosterically induced changes on stability and communications in the residue interaction networks.

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“…The efficacy of a drug molecule is largely dependent on molecular interactions at the active site ( Schiebel et al, 2018 ; Mishra et al, 2021 ), and the network of H-bonds plays a crucial role in this interaction. Thus, H-bond interactions between ExoN and drug molecules were calculated ( Chen et al, 2016 ).…”

Section: Resultsmentioning

confidence: 99%

Combining SARS-CoV-2 Proofreading Exonuclease and RNA-Dependent RNA Polymerase Inhibitors as a Strategy to Combat COVID-19: A High-Throughput in silico Screening

Khater

Kumar

Dasgupta³

et al. 2021

Front. Microbiol.

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected millions of people worldwide. Currently, many clinical trials in search of effective COVID-19 drugs are underway. Viral RNA-dependent RNA polymerase (RdRp) remains the target of choice for prophylactic or curative treatment of COVID-19. Nucleoside analogs are the most promising RdRp inhibitors and have shown effectiveness in vitro, as well as in clinical settings. One limitation of such RdRp inhibitors is the removal of incorporated nucleoside analogs by SARS-CoV-2 exonuclease (ExoN). Thus, ExoN proofreading activity accomplishes resistance to many of the RdRp inhibitors. We hypothesize that in the absence of highly efficient antivirals to treat COVID-19, combinatorial drug therapy with RdRp and ExoN inhibitors will be a promising strategy to combat the disease. To repurpose drugs for COVID-19 treatment, 10,397 conformers of 2,240 approved drugs were screened against the ExoN domain of nsp14 using AutoDock VINA. The molecular docking approach and detailed study of interactions helped us to identify dexamethasone metasulfobenzoate, conivaptan, hesperidin, and glycyrrhizic acid as potential inhibitors of ExoN activity. The results were further confirmed using molecular dynamics (MD) simulations and molecular mechanics combined with generalized Born model and solvent accessibility method (MM-GBSA) calculations. Furthermore, the binding free energy of conivaptan and hesperidin, estimated using MM-GBSA, was −85.86 ± 0.68 and 119.07 ± 0.69 kcal/mol, respectively. Based on docking, MD simulations and known antiviral activities, and conivaptan and hesperidin were identified as potential SARS-CoV-2 ExoN inhibitors. We recommend further investigation of this combinational therapy using RdRp inhibitors with a repurposed ExoN inhibitor as a potential COVID-19 treatment.

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Identifying the natural polyphenol catechin as a multi-targeted agent against SARS-CoV-2 for the plausible therapy of COVID-19: an integrated computational approach

Cited by 80 publications

References 84 publications

Identification and characterization of mutations in the SARS-CoV-2 RNA-dependent RNA polymerase as a promising antiviral therapeutic target

Identification and characterization of mutations in the SARS-CoV-2 RNA-dependent RNA polymerase as a promising antiviral therapeutic target

Computational analysis of protein stability and allosteric interaction networks in distinct conformational forms of the SARS-CoV-2 spike D614G mutant: reconciling functional mechanisms through allosteric model of spike regulation

Combining SARS-CoV-2 Proofreading Exonuclease and RNA-Dependent RNA Polymerase Inhibitors as a Strategy to Combat COVID-19: A High-Throughput in silico Screening

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