Molecular Dynamics Simulation of Privileged Biflavonoids as SARS-CoV2 3CLpro Targeting Agents

Abstract

According to the limited medications for COVID-19, natural products gained increasing attention. Scientific indications revealed the effect of biflavonoids (BFs) against respiratory syndrome viruses. The functional importance of 3-chymotrypsin-like protease (3CLpro) in forming viral RNA raises its potential to be targeted in SARS-CoV2. This study is devoted to the computational analysis of privileged BFs within the SARS-CoV2 3CLpro active site. Docking and molecular dynamics (MD) simulations were collectively used to explore the most probable binding modes and stable ligand–enzyme chemical interactions. Despite the structural resemblance, a wide range of binding affinities was retrieved for BFs ([Formula: see text][Formula: see text]kcal/mol). Garciniaflavone C ([Formula: see text][Formula: see text]kcal/mol), 7,7[Formula: see text], 4[Formula: see text]-tri-O-methylagathisflavone ([Formula: see text][Formula: see text]kcal/mol) and 8,8[Formula: see text]-biapigenil ([Formula: see text][Formula: see text]kcal/mol) were top enzyme binders. The stability of acquired complexes was analyzed through 50-ns all-atom MD simulations. Garciniaflavone C, 7,7[Formula: see text], 4[Formula: see text]-tri-O-methylagathisflavone and 8,8[Formula: see text]-biapigenil showed 29%, 22% and 23% persevered binding residues, respectively. SARS-CoV2-garciniaflavone C complex was mediated by several nonpolar interactions. MD simulations assigned H-bond interaction between the catalytic dyad residue Cys145 and garciniaflavone C. 7,7[Formula: see text], 4[Formula: see text]-tri-O-methylagathisflavone participated in a [Formula: see text]-cation interaction to His41. Solvent accessible surface area distribution indicated the sufficiency of MD simulation time (50[Formula: see text]ns) to screen equilibrated complex systems. Although a detailed pharmacological mechanism is to be elucidated, our findings indicated superior binding stability of 7,7[Formula: see text], 4[Formula: see text]-tri-O-methylagathisflavone within SARS-CoV2 active site. While the biological function of the majority of BF derivatives remains to be elucidated, results of the current study revealed key structural features and potentials of privileged BFs for further structure-guided optimization toward potent SARS-CoV2 3CLpro inhibitors.