Molecular docking and dynamic simulation of marine natural products from soft coral-derived microbes against SARS-CoV-2 main protease and spike protein

Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Two key therapeutic target proteins of SARS-CoV-2, the Spike (S) protein and the main protease (Mpro), facilitate the entry of virus and its replication inside the host cell, respectively. Notably, several pointmutations in the receptor-binding domain (RBD) of the S-protein have led to the origin of different SARS-CoV-2 Variants of Concern (VOCs) including Alpha (B.1.1.7), Beta (B.1.351), Delta (B.1.617.2), Gamma (P.1), and Omicron (B.1.1.529). The low efficacy of currently available antiviral drugs against these VOCs highlights the need for screening and discovery of novel natural compounds against COVID-19. This study performed molecular docking of marine natural products from soft coral-derived microbes against the Mpro and the RBD of the S-protein from wild type (WT) and five VOCs. Many of the test compounds [e.g., Cottoquinazoline B and D (CQB/D), Tetraorcinol A (TOA), Versicoloritide A and C (VCA/C), Fumiquinazoline K, and Pencillanthranin A) showed stronger binding affinities compared to control antiviral drugs (nelfinavir and remdesivir) and formed favorable interactions with both Mpro and the RBD of S-protein. ADMET analysis revealed that most of the best-docked compounds obey Lipinski rule of five. Molecular dynamics (MD) simulation (200 ns) analysis further revealed stable binding conformations of the top docked complexes of (1) CQB with Mpro, (2) CQB with the RBD of WT S-protein, (3) TOA with the RBD of S-protein from beta variant (4) TOA with the RBD of S-protein from Omicron variant, (5) TOA with the RBD of S-protein from Delta variant, (6) TOA with the RBD of S-protein from Gamma variant, and (7) VCA with the RBD of alpha variant. However, future in vitro and in vivo studies are still required to validate efficacy of these compounds.