Investigating the Structure-Activity Relationship of Laulimalides Marine Macrolides as Promising Inhibitors for SARS-CoV-2 Main Protease (Mpro)

Abstract

SARS-CoV-2, the new coronavirus variant, has been a worldwide health crisis that may outbreak at any time in the future. Over spans of human history, preparations derived from natural products have always been recognized as a preliminary source of medications. Taking into account the SARS-CoV-2 main protease (Mpro) as the essential element of the viral cycle and as a main target, herein we highlight a computer-aided comprehensive virtual screening for a focused chemical list of 14 laulimalides marine macrolides against SARS-CoV-2 Mpro using a set of integrated modern computational techniques including molecular docking (MDock), molecule dynamic simulations (MDS) and structure-activity relationships (SARs). Based on their remarkable ligand-protein energy scores and relevant binding affinities with SARS-CoV-2 (Mpro) pocket residues, two promising macrolides [laulimalides LA4 (6) and LA18 (13)] are selected as proposed inhibitor compounds. Consequently, they are thermodynamically investigated by deciphering their MD simulations at 100 ns, where they show noticeable stability within the accommodated (Mpro) pockets. Moreover, in-depth SARs studies suggest crucial roles for C-23 substituted side chain and C-20 methoxy as essential pharmacophoric structural features for activity. Further in vitro/vivo examinations of the selected marine macrolides would pave the way towards developing effective antiviral drugs from natural resources.