Investigating the structure-activity relationship of marine polycyclic batzelladine alkaloids as promising inhibitors for SARS-CoV-2 main protease (Mpro)

• Published in: Computers in biology and medicine 2022-08, Vol.147, p.105738-105738, Article 105738
• Main Authors: Elgohary, Alaa M., Elfiky, Abdo A., Pereira, Florbela, Abd El-Aziz, Tarek Mohamed, Sobeh, Mansour, Arafa, Reem K., El-Demerdash, Amr
• Format: Article
• Language: English
• Subjects: Alkaloids; Alkaloids - pharmacology; Antiviral agents; Antiviral Agents - chemistry; Antiviral drugs; Batzelladines; Binding sites; Cancer; Computer applications; Coronavirus 3C Proteases; Coronaviruses; COVID-19; COVID-19 Drug Treatment; Drugs; Economic crisis; Fatty acids; Guanidine alkaloids; Humans; Leukemia; Libraries; Ligands; Lymphoma; Marine sponges; Molecular docking; Molecular Docking Simulation; Molecular dynamics; Molecular Dynamics Simulation; Molecular structure; Multiple myeloma; Natural products; Pandemics; Peptides; Pharmaceutical industry; Protease; Protease inhibitors; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacology; Proteinase; Proteinase inhibitors; Proteins; SARs; SARS-CoV-2; Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Software; Structure-Activity Relationship; Structure-activity relationships; Vaccines; Viral diseases; Viral Nonstructural Proteins - chemistry; Viruses
• ISSN: 0010-4825; 1879-0534
• DOI: 10.1016/j.compbiomed.2022.105738

Over a span of two years ago, since the emergence of the first case of the novel coronavirus (SARS-CoV-2) in China, the pandemic has crossed borders causing serious health emergencies, immense economic crisis and impacting the daily life worldwide. Despite the discovery of numerous forms of precautionary vaccines along with other recently approved orally available drugs, yet effective antiviral therapeutics are necessarily needed to hunt this virus and its variants. Historically, naturally occurring chemicals have always been considered the primary source of beneficial medications. Considering the SARS-CoV-2 main protease (Mpro) as the duplicate key element of the viral cycle and its main target, in this paper, an extensive virtual screening for a focused chemical library of 15 batzelladine marine alkaloids, was virtually examined against SARS-CoV-2 main protease (Mpro) using an integrated set of modern computational tools including molecular docking (MDock), molecule dynamic (MD) simulations and structure-activity relationships (SARs) as well. The molecular docking predictions had disclosed four promising compounds including batzelladines H–I (8–9) and batzelladines F-G (6–7), respectively according to their prominent ligand-protein energy scores and relevant binding affinities with the (Mpro) pocket residues. The best two chemical hits, batzelladines H–I (8–9) were further investigated thermodynamically though studying their MD simulations at 100 ns, where they showed excellent stability within the accommodated (Mpro) pocket. Moreover, SARs studies imply the crucial roles of the fused tricyclic guanidinic moieties, its degree of unsaturation, position of the N–OH functionality and the length of the side chain as a spacer linking between two active sites, which disclosed fundamental structural and pharmacophoric features for efficient protein-ligand interaction. Such interesting findings are greatly highlighting further in vitro/vivo examinations regarding those marine natural products (MNPs) and their synthetic equivalents as promising antivirals. [Display omitted] •COVID-19 is unprecedented health crisis that exploded globally late 2019.•Marine natural products (MNPs) are powerful chemical tools that might be able to compete COVID-19 outbreak.•Extensive computational screening supported with structure-activity relationships (SARs) studies recommended the marine batzelladine alkaloids, particularly batzelladines H–I (8–9) as promising antiviral hits for