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The recent outbreak of novel “coronavirus disease 2019†(COVID-19) has spread rapidly /worldwide, causing a global pandemic In the absence of a vaccine or a suitable /chemotherapeutic intervention, it is an urgent need to develoa new antiviral drug to fight this /deadly respiratory disease 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 (Mpro /or 3CLpro) by using all-atom molecular dynamics simulations and free energy calculations We /calculated the total binding free energy (ΔGbind) of both inhibitors and further decomposed /ΔGbind into various forces governing the complex formation using the Molecular /Mechanicsoisson-Boltzmann Surface Area (MMBSA) method Our calculations reveal /that α-ketoamide is more potent (ΔGbind= - 9 05 kcal/mol) compared to Z31792168 (ΔGbind= - /3 25 kcal/mol) against COVID-19 3CLpro The increase in ΔGbind for α-ketoamide relative to /Z31792168 arises due to an increase in the favorable electrostatic and van der Waals /interactions between the inhibitor and 3CLpro Further, we have identified important residues /controlling the 3CLpro-ligand binding from per-residue based decomposition of the binding free /energy Finally, we have compared ΔGbind 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 both lopinavir and darunavir In the case of lopinavir, a decrease in the size of the 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 helin designing rational anticoronaviral drugs targeting the SARS-CoV-2 main /protease /div
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