Investigating specificity of the anti-hypertensive inhibitor WNK463 against With-No-Lysine kinase family isoforms via multiscale simulations

Jonniya, Nisha Amarnath; Kar, Parimal

doi:10.1080/07391102.2019.1602079

Cited by 30 publications

(24 citation statements)

References 75 publications

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“…The binding affinity of EGCG, TF1, TF3, TF2b, TF2a, hesperidin, myricetin, quercetagetin, and remdesivir against the SARS-CoV-2 RdRp, were calculated by the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) methodology (Jonniya & Kar, 2020 ; Kar, Seel, et al., 2007 ; Kar, Wei, et al., 2007 ; Kar et al., 2011 ; 2013 ; Kar & Knecht, 2012a , 2012b , 2012c , 2012d ; Kollman et al., 2000 ; Roy et al., 2020 ; Wang et al., 2006 ). The MM-PBSA scheme can briefly be described as follows: where are the changes in molecular mechanical energy, solvation free energy, and conformational entropy, respectively.…”

Section: Methodsmentioning

confidence: 99%

Plant-derived natural polyphenols as potential antiviral drugs against SARS-CoV-2viaRNA‐dependent RNA polymerase (RdRp) inhibition: anin-silicoanalysis

Singh

Sonawane

et al. 2020

Journal of Biomolecular Structure and Dynamics

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113

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The sudden outburst of Coronavirus disease (COVID-19) caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) poses a massive threat to global public health. Currently, no therapeutic drug or vaccine exists to treat COVID-19. Due to the time taking process of new drug development, drug repurposing might be the only viable solution to tackle COVID-19. RNA-dependent RNA polymerase (RdRp) catalyzes SARS-CoV-2 RNA replication and hence, is an obvious target for antiviral drug design. Interestingly, several plant-derived polyphenols effectively inhibit the RdRp of other RNA viruses. More importantly, polyphenols have been used as dietary supplementations for a long time and played beneficial roles in immune homeostasis. We were curious to study the binding of polyphenols with SARS-CoV-2 RdRp and assess their potential to treat COVID-19. Herein, we made a library of polyphenols that have shown substantial therapeutic effects against various diseases. They were successfully docked in the catalytic pocket of RdRp. The investigation reveals that EGCG, theaflavin (TF1), theaflavin-3'-O-gallate (TF2a), theaflavin-3'-gallate (TF2b), theaflavin 3,3'-digallate (TF3), hesperidin, quercetagetin, and myricetin strongly bind to the active site of RdRp. Further, a 150-ns molecular dynamic simulation revealed that EGCG, TF2a, TF2b, TF3 result in highly stable bound conformations with RdRp. The binding free energy components calculated by the MM-PBSA also confirm the stability of the complexes. We also performed a detailed analysis of ADME prediction, toxicity prediction, and target analysis for their druggability. Overall, our results suggest that EGCG, TF2a, TF2b, TF3 can inhibit RdRp and represent an effective therapy for COVID-19.

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Section: Methodsmentioning

confidence: 99%

Plant-derived natural polyphenols as potential antiviral drugs against SARS-CoV-2viaRNA‐dependent RNA polymerase (RdRp) inhibition: anin-silicoanalysis

Singh

Sonawane

et al. 2020

Journal of Biomolecular Structure and Dynamics

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113

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“…MMPBSA.py script available in the AmberTools19 was used for the analysis. Details of the MM-PBSA protocol were provided in our previous studies (Kar and Knecht, 2012a , b , c , d ; Kar et al, 2013 ; Jonniya et al, 2019 ; Jonniya and Kar, 2020 ; Roy et al, 2020 ; Sk et al, 2020a , d ), and the same protocol was adopted here.…”

Section: Methodsmentioning

confidence: 99%

“…Further, the decomposition of the total binding free energy at the residue level was conducted by using the Molecular Mechanics Generalized Born Surface Area (MM-GBSA) scheme (Kar and Knecht, 2012a , b , c ; Kar et al, 2013 ; Jonniya and Kar, 2020 ) as per the following equation.…”

Section: Methodsmentioning

confidence: 99%

Computational Investigation of Structural Dynamics of SARS-CoV-2 Methyltransferase-Stimulatory Factor Heterodimer nsp16/nsp10 Bound to the Cofactor SAM

Jonniya

Roy

et al. 2020

Front. Mol. Biosci.

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Recently, a highly contagious novel coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, has emerged, posing a global threat to public health. Identifying a potential target and developing vaccines or antiviral drugs is an urgent demand in the absence of approved therapeutic agents. The 5′-capping mechanism of eukaryotic mRNA and some viruses such as coronaviruses (CoVs) are essential for maintaining the RNA stability and protein translation in the virus. SARS-CoV-2 encodes S-adenosyl-L-methionine (SAM) dependent methyltransferase (MTase) enzyme characterized by nsp16 (2′-O-MTase) for generating the capped structure. The present study highlights the binding mechanism of nsp16 and nsp10 to identify the role of nsp10 in MTase activity. Furthermore, we investigated the conformational dynamics and energetics behind the binding of SAM to nsp16 and nsp16/nsp10 heterodimer by employing molecular dynamics simulations in conjunction with the Molecular Mechanics Poisson-Boltzmann Surface Area (MM/PBSA) method. We observed from our simulations that the presence of nsp10 increases the favorable van der Waals and electrostatic interactions between SAM and nsp16. Thus, nsp10 acts as a stimulator for the strong binding of SAM to nsp16. The hydrophobic interactions were predominately identified for the nsp16-nsp10 interactions. Also, the stable hydrogen bonds between Ala83 (nsp16) and Tyr96 (nsp10), and between Gln87 (nsp16) and Leu45 (nsp10) play a vital role in the dimerization of nsp16 and nsp10. Besides, Computational Alanine Scanning (CAS) mutagenesis was performed, which revealed hotspot mutants, namely I40A, V104A, and R86A for the dimer association. Hence, the dimer interface of nsp16/nsp10 could also be a potential target in retarding the 2′-O-MTase activity in SARS-CoV-2. Overall, our study provides a comprehensive understanding of the dynamic and thermodynamic process of binding nsp16 and nsp10 that will contribute to the novel design of peptide inhibitors based on nsp16.

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“…In order to estimate the stabilization of binding systems, the binding free energies or affinity of all inhibitors against SARS-CoV-2 3CL pro were calculated by the widely used molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method (Kollman et al, 2000;Wang et al, 2001;Kar et al, 2011;Kar & Knecht, 2012a;Kar & Knecht, 2012b;Kar & Knecht, 2012c;Kar & Knecht, 2012d;Kar et al, 2013). We discussed the MMPBSA scheme in detail in our previous studies (Jonniya et al, 2019;Jonniya & Kar, 2020;Roy et al, 2020;Sk et al, 2020) and here we used the same protocol. Briefly, in the MMPBSA scheme, the binding free energy (DG bind ) of an inhibitor is calculated by utilizing the following equations:…”

Section: Energy Calculationsmentioning

confidence: 99%

Elucidating biophysical basis of binding of inhibitors to SARS-CoV-2 main protease by using molecular dynamics simulations and free energy calculations

Roy

Jonniya

et al. 2020

Journal of Biomolecular Structure and Dynamics

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The recent outbreak of novel "coronavirus disease 2019" (COVID-19) has spread rapidly worldwide, causing a global pandemic. In the present work, we have elucidated the mechanism of binding of two inhibitors, namely a-ketoamide and Z31792168, to SARS-CoV-2 main protease (M pro or 3CL pro ) by using all-atom molecular dynamics simulations and free energy calculations. We calculated the total binding free energy (DG bind ) of both inhibitors and further decomposed DG bind into various forces governing the complex formation using the Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) method. Our calculations reveal that a-ketoamide is more potent (DG bind ¼ À 9.05 kcal/mol) compared to Z31792168 (DG bind ¼ À 3.25 kcal/mol) against COVID-19 3CL pro . The increase in DG bind for a-ketoamide relative to Z31792168 arises due to an increase in the favorable electrostatic and van der Waals interactions between the inhibitor and 3CL pro . Further, we have identified important residues controlling the 3CL pro -ligand binding from per-residue based decomposition of the binding free energy. Finally, we have compared DG bind of these two inhibitors with the anti-HIV retroviral drugs, such as lopinavir and darunavir. It is observed that a-ketoamide is more potent compared to lopinavir and darunavir. In the case of lopinavir, a decrease in van der Waals interactions is responsible for the lower binding affinity compared to a-ketoamide. On the other hand, in the case of darunavir, a decrease in the favorable intermolecular electrostatic and van der Waals interactions contributes to lower affinity compared to a-ketoamide. Our study might help in designing rational anti-coronaviral drugs targeting the SARS-CoV-2 main protease.

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Investigating specificity of the anti-hypertensive inhibitor WNK463 against With-No-Lysine kinase family isoforms via multiscale simulations

Cited by 30 publications

References 75 publications

Plant-derived natural polyphenols as potential antiviral drugs against SARS-CoV-2viaRNA‐dependent RNA polymerase (RdRp) inhibition: anin-silicoanalysis

Plant-derived natural polyphenols as potential antiviral drugs against SARS-CoV-2viaRNA‐dependent RNA polymerase (RdRp) inhibition: anin-silicoanalysis

Computational Investigation of Structural Dynamics of SARS-CoV-2 Methyltransferase-Stimulatory Factor Heterodimer nsp16/nsp10 Bound to the Cofactor SAM

Elucidating biophysical basis of binding of inhibitors to SARS-CoV-2 main protease by using molecular dynamics simulations and free energy calculations

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