Unraveling the binding mechanism of the active form of Remdesivir to RdRp of SARS-CoV-2 and designing new potential analogues: Insights from molecular dynamics simulations

Muhammad Arba; Nicholas Paradis; Setyanto T Wahyudi; Dylan J Brunt; Katherine R Hausman; Phillip M Lakernick; Mursalin Singh; Chun Wu

doi:10.1016/j.cplett.2022.139638

Unraveling the binding mechanism of the active form of Remdesivir to RdRp of SARS-CoV-2 and designing new potential analogues: Insights from molecular dynamics simulations

Chem Phys Lett. 2022 Jul 16:799:139638. doi: 10.1016/j.cplett.2022.139638. Epub 2022 Apr 20.

Authors

Muhammad Arba¹, Nicholas Paradis², Setyanto T Wahyudi³, Dylan J Brunt², Katherine R Hausman², Phillip M Lakernick², Mursalin Singh², Chun Wu²

Affiliations

¹ Faculty of Pharmacy, Universitas Halu Oleo, Kendari 93232, Indonesia.
² Department of Molecular & Cellular Biosciences, College of Science and Mathematics, Rowan University, Glassboro, NJ 08028, United States.
³ Department of Physics, Faculty of Mathematic and Natural Sciences, IPB University, Bogor 16680, Indonesia.

Abstract

The binding of the active form of Remdesivir (RTP) to RNA-dependent RNA Polymerase (RdRp) of SARS-CoV-2 was studied using molecular dynamics simulation. The RTP maintained the interactions observed in the experimental cryo-EM structure. Next, we designed new analogues of RTP, which not only binds to the RNA primer strand in a similar pose as that of RTP, but also binds more strongly than RTP does as predicted by MM-PBSA binding energy. This suggest that these analogues might be able to covalently link to the primer strand as RTP, but their 3' modification would terminate the primer strand growth.

Keywords: Binding mechanism; Molecular Dynamics Simulations; RNA polymerization inhibitor; RdRp; Remdesivir derivatives.