tetano
Editor, Senior Moderator
J Biomol Struct Dyn. 2020 May 12:1-21. doi: 10.1080/07391102.2020.1768149. [Epub ahead of print]
Elucidating biophysical basis of binding of inhibitors to SARS-CoV-2 main protease by using molecular dynamics simulations and free energy calculations.
Sk MF[SUP]1[/SUP], Roy R[SUP]1[/SUP], Jonniya NA[SUP]1[/SUP], Poddar S[SUP]1[/SUP], Kar P[SUP]1[/SUP].
Author information
Abstract
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 α-ketoamide and Z31792168, to SARS-CoV-2 main protease (M[SUP]pro[/SUP] or 3CL[SUP]pro[/SUP]) by using all-atom molecular dynamics simulations and free energy calculations. We calculated the total binding free energy (ΔG[SUB]bind[/SUB]) of both inhibitors and further decomposed ΔG[SUB]bind[/SUB] into various forces governing the complex formation using the Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) method. Our calculations reveal that α-ketoamide is more potent (ΔG[SUB]bind[/SUB]= - 9.05 kcal/mol) compared to Z31792168 (ΔG[SUB]bind[/SUB]= - 3.25 kcal/mol) against COVID-19 3CL[SUP]pro[/SUP]. The increase in ΔG[SUB]bind[/SUB] for α-ketoamide relative to Z31792168 arises due to an increase in the favorable electrostatic and van der Waals interactions between the inhibitor and 3CL[SUP]pro[/SUP]. Further, we have identified important residues controlling the 3CL[SUP]pro[/SUP]-ligand binding from per-residue based decomposition of the binding free energy. Finally, we have compared ΔG[SUB]bind[/SUB] of these two inhibitors with the anti-HIV retroviral drugs, such as lopinavir and darunavir. It is observed that α-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 α-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 α-ketoamide. Our study might help in designing rational anti-coronaviral drugs targeting the SARS-CoV-2 main protease.
KEYWORDS:
Binding Free Energy; COVID-19; MM-PBSA; Molecular Dynamics; SARS-CoV-2 3CLpro
PMID:32396767DOI:10.1080/07391102.2020.1768149
Elucidating biophysical basis of binding of inhibitors to SARS-CoV-2 main protease by using molecular dynamics simulations and free energy calculations.
Sk MF[SUP]1[/SUP], Roy R[SUP]1[/SUP], Jonniya NA[SUP]1[/SUP], Poddar S[SUP]1[/SUP], Kar P[SUP]1[/SUP].
Author information
Abstract
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 α-ketoamide and Z31792168, to SARS-CoV-2 main protease (M[SUP]pro[/SUP] or 3CL[SUP]pro[/SUP]) by using all-atom molecular dynamics simulations and free energy calculations. We calculated the total binding free energy (ΔG[SUB]bind[/SUB]) of both inhibitors and further decomposed ΔG[SUB]bind[/SUB] into various forces governing the complex formation using the Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) method. Our calculations reveal that α-ketoamide is more potent (ΔG[SUB]bind[/SUB]= - 9.05 kcal/mol) compared to Z31792168 (ΔG[SUB]bind[/SUB]= - 3.25 kcal/mol) against COVID-19 3CL[SUP]pro[/SUP]. The increase in ΔG[SUB]bind[/SUB] for α-ketoamide relative to Z31792168 arises due to an increase in the favorable electrostatic and van der Waals interactions between the inhibitor and 3CL[SUP]pro[/SUP]. Further, we have identified important residues controlling the 3CL[SUP]pro[/SUP]-ligand binding from per-residue based decomposition of the binding free energy. Finally, we have compared ΔG[SUB]bind[/SUB] of these two inhibitors with the anti-HIV retroviral drugs, such as lopinavir and darunavir. It is observed that α-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 α-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 α-ketoamide. Our study might help in designing rational anti-coronaviral drugs targeting the SARS-CoV-2 main protease.
KEYWORDS:
Binding Free Energy; COVID-19; MM-PBSA; Molecular Dynamics; SARS-CoV-2 3CLpro
PMID:32396767DOI:10.1080/07391102.2020.1768149