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 is a world-wide health crisis. 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 main protease (Mpro) using a set of integrated modern computational techniques including molecular docking (MDock), molecule dynamic simulations (MDS) and structure-activity relationships (SARs) as well. Indeed, computational studies had disclosed two promising macrolides [laulimalides LA4 (6) and LA18 (13)] based on their remarkable ligand-protein energy scores and relevant binding affinities with the SARS-CoV-2 (Mpro) pocket residues. Consequentially, the two compounds were further investigated thermodynamically though deciphering their MD simulations at 100 ns, where they showed noticeable stability within the accommodated (Mpro) pockets. Moreover, in-deep SARs studies suggested the crucial roles of the C-23 subistituted side chain and the C-20 methoxy as essential pharmacophoric structural features for activity. Such interesting outcomes are highly recommending further in vitro/vivo examinations regarding those marine macrolides and open a gate towards developing more effective antivirals drug leads.