Korupensamine A, but Not Its Atropisomer, Korupensamine B, Inhibits SARS-CoV-2 in Vitro by Targeting Its Main Protease (Mpro).

By combining docking and molecular dynamics simulations, we explored a library of 65 mostly axially naphthylisoquinoline alkaloids and their analogues, with most different molecular architectures and structural analogues, for their activity against SARS-CoV-2. Although natural biaryls are often regarded without consid-eration of their axial chirality, they can bind to protein targets in an atroposelective manner. By combining docking results with steered molecular dynamics simulations, we identified one alkaloid, korupensamine A, atropisomer-specifically inhibited the main protease (Mpro) activity of SARS-CoV-2 significantly in comparison the reference covalent inhibitor GC376 (IC50 = 2.52 +/- 0.14 and 0.88 +/- 0.15 mu M, respectively) and reduced growth by five orders of magnitude in vitro (EC50 = 4.23 +/- 1.31 mu M). To investigate the binding pathway mode of interaction of korupensamine A within the active site of the protease, we utilized Gaussian accelerated molecular dynamics simulations, which reproduced the docking pose of korupensamine A inside the active