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 (ΔGb−7.11−12.66kcal/mol). Garciniaflavone C (ΔGb−12.66kcal/mol), 7,7′′, 4′′′-tri-O-methylagathisflavone (ΔGb−12.16kcal/mol) and 8,8′′-biapigenil (ΔGb−12.08kcal/mol) were top enzyme binders. The stability of acquired complexes was analyzed through 50-ns all-atom MD simulations. Garciniaflavone C, 7,7′′, 4′′′-tri-O-methylagathisflavone and 8,8′′-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′′, 4′′′-tri-O-methylagathisflavone participated in a π-cation interaction to His41. Solvent accessible surface area distribution indicated the sufficiency of MD simulation time (50ns) to screen equilibrated complex systems. Although a detailed pharmacological mechanism is to be elucidated, our findings indicated superior binding stability of 7,7′′, 4′′′-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. [ FROM AUTHOR] Copyright of Journal of Computational Biophysics & Chemistry is the property of World Scientific Publishing Company and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)