Comparative MD Study of Inhibitory Activity of Opaganib and Adamantane-Isothiourea Derivatives toward COVID-19 Main Protease Mpro.

Abstract

In this study, the inhibitory potency of four adamantly‐ isothiourea derivatives (compounds 1 [4‐bromobenzyl (Z)‐N′‐(adamantan‐1‐yl)‐4‐phenylpiperazine‐1‐carbothioimidate], 2 [3,5‐bis(trifluoromethyl)benzyl (Z)‐N′‐(adamantan‐1‐yl)‐4‐phenylpiperazine‐1‐carbothioimidate], 3 [4‐bromobenzyl (Z)‐N‐(adamantan‐1‐yl)morpholine‐4‐carbothioimidate] and 4 [3,5‐bis(trifluoromethyl)benzyl (Z)‐N‐(adamantan‐1‐yl)morpholine‐4‐carbothioimidate]) was evaluated against SARS‐CoV‐2 targeted proteins. The investigated compounds 1–4 possess a similar structure to opaganib, which is used in studies like a potential drug for COVID‐19 treatment. Since examined adamantly‐isothiourea derivatives (1–4) shown broad‐spectrum of antibacterial activity and significant in vitro cytotoxic effects against five human tumor cell lines and shown similarity in structure with opaganib, it was of interest to study their inhibitory potency toward some SARS‐CoV‐2 proteins such as SARS‐CoV‐2 main protease Mpro and mutation of SARS‐CoV‐2 Spike (S) Protein D614G. The inhibitory potency of studied compounds is examined using molecular docking and molecular dynamic simulations. The results of molecular docking simulations indicate compound 1 as the most prominent candidate of inhibition of SARS‐CoV‐2 main protease Mpro (▵Gbind=11.24 kcal/mol), while almost the same inhibition potency of all studied compounds is exhibited toward D614G. Regarding the results obtained by molecular dynamic simulations, compounds 1 and 4 possess similar inhibitory potency toward SARS‐CoV‐2 main protease Mpro as opaganib (▵Gbind ≈ 40 kcal/mol).