Inspection on the Mechanism of SARS-CoV-2 Inhibition by Penciclovir: A Molecular Dynamic Study

Abstract

In recent years, humanity has had to face a critical pandemic due to SARS-CoV-2. In the rapid search for effective drugs against this RNA-positive virus, the repurposing of already existing nucleotide/nucleoside analogs able to stop RNA replication by inhibiting the RNA-dependent RNA polymerase enzyme has been evaluated. In this process, a valid contribution has been the use of in silico experiments, which allow for a rapid evaluation of the possible effectiveness of the proposed drugs. Here we propose a molecular dynamic study to provide insight into the inhibition mechanism of Penciclovir, a nucleotide analog on the RNA-dependent RNA polymerase enzyme. Besides the presented results, in this article, for the first time, molecular dynamic simulations have been performed considering not only the RNA-dependent RNA polymerase protein, but also its cofactors (fundamental for RNA replication) and double-strand RNA.

Trapping a non-cognate nucleotide upon initial binding for replication fidelity control in SARS-CoV-2 RNA dependent RNA polymerase

“…18,35,36 Computational docking has often been employed, which predominantly focuses on nucleotide immediate binding to an apo-form RdRp structure, 37,38 non-differentiating the active open or closed form, and initially largely overlooking the functional RdRp (nsp12) elongation complex composed additionally of nsp8, nsp7, and RNA strands. 39 Moreover, while atomic molecular dynamics (MD) studies have provided insights into interactions of nucleotide analogues with the viral RdRp, they often directly utilize the insertion state, 40–42 ignoring the initial nucleotide analogue binding stage that can be essential for nucleotide screening or selectivity upon entry. Meanwhile, single-molecule studies have offered a glimpse into the dynamics of the elongation cycle, revealing that RdRp can adopt fast, slow, or very slow catalytic pathways with variable rates contingent upon the kinetic pathway.…”

Investigation of protein-protein interactions and hotspot region on the NSP7-NSP8 binding site in NSP12 of SARS-CoV-2

“…Due to its key role in the viral cycle, several papers have been published aiming to provide alternatives for inhibiting NSP12 function ( Elkarhat et al, 2022 ; Bagabir, 2023 ; Giannetti et al, 2023 ; Gu et al, 2023 ). However, up to now, the FDA only approved the antivirals Molnupiravir and remdesivir targeting NSP12, both acting in different ways, with the last being covalently incorporated into the primer strand of replicating viral RNA, terminating chain elongation ( Kabinger et al, 2021 ).…”

Trapping non-cognate nucleotide upon initial binding for replication fidelity control in SARS-CoV-2 RNA dependent RNA polymerase

“…Computational docking has often been employed, which predominantly focus on nucleotide immediate binding to an apo-form RdRp structure [34,35], non-differentiating the active open or closed form, and overlooking initially the functional RdRp (nsp12) elongation complex composed additionally of nsp8, nsp7, and RNA strands. Moreover, while atomic molecular dynamics (MD) studies have provided insights into interactions of nucleotide analogues with the viral RdRp, they often utilize directly the insertion state [36][37][38], ignoring the initial nucleotide analogue binding stage that can be essential for nucleotide screening or selectivity upon entry. Meanwhile, single-molecule studies have offered a glimpse into the dynamics of the elongation cycle, revealing that RdRp can adopt fast, slow, or very slow catalytic pathways with variable rates contingent upon the kinetic pathway [39].…”