Investigating the Antiviral Therapeutic Potentialities of Marine Polycyclic Lamellarin Pyrrole Alkaloids as Promising Inhibitors for SARS-CoV-2 and Zika Main Proteases (Mpro)

Abstract

The new coronavirus variant (SARS-CoV-2) and Zika virus are two worldwide health pandemics which outbreak borders and causing significant health difficulties, severe economic problems, and disturbing people’s daily life globally. Although many forms of preventative vaccines have been discovered and approved as protective manipulations alongside several orally available medications to stop the viral explosion, parallel competent antivirals are vitally needed to compete these viruses and their forms. Along history, naturally occurring organic chemicals have always crucially recognized as a main source of valuable medications. Taking into consideration the SARS-CoV-2 and Zika main proteases (Mpro) as the re-production key element of the viral cycle and its main target, herein we report an intensive computer-aided virtual screening for a focused list of 39 marine lamellarins pyrrole alkaloids, against SARS-CoV-2 and Zika main proteases (Mpro) using a set of combined modern computational methodologies including molecular docking (MDock), molecule dynamic simulations (MDS) and structure-activity relationships (SARs) as well. Indeed, the molecular docking studies had revealed four promising marine alkaloids including [lamellarin H (14)/lamellarin K (17)] and [lamellarin S (26)/ lamellarin Z (39)], according to their notable ligand-protein energy scores and relevant binding affinities with the SARS-CoV-2 and Zika (Mpro) pocket residues, respectively. Consequentially, these four chemical hits were further examined thermodynamically though investigating their MD simulations at 100 ns, where they showed prominent stability within the accommodated (Mpro) pockets. Moreover, in-deep SARs studies suggested the crucial roles of the rigid fused polycyclic ring system, particularly aromatic A- and F- rings, position of the phenolic -OH and -lactone functionalities as essential structural and pharmacophoric characteristics for an effective protein ligand interaction against SARS-CoV-2 and Zika Mpro, respectively. These motivating outcomes are greatly recommending further in vitro/vivo examinations regarding those marine derived compounds and their synthetic congeners, opening the gate to identify clinically useful antivirals based or bio-inspired from lamellarins pyrrole alkaloids (LPAs).

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

“…Thus, core bridgeheads between biological effectiveness and quantitative structure activity relationships could be consequently established (Alaa M Pereira et al, 2022). In this study, we comprehensively explore virtually a concise library of fourteen laulimalides marine-containing macrolides against SARS-CoV-2 main protease (Mpro) dimer using state-of-the-art of integrated computational tools including molecular docking, molecular dynamics (MD) simulations, binding free energy and SARs.…”