Korupensamine A, but not its atropisomer, korupensamine B, inhibits SARS-CoV-2 in vitro by targeting its main protease (Mpro)

• Published in: European journal of medicinal chemistry 2023-05, Vol.251, p.115226-115226, Article 115226
• Main Authors: Sayed, Ahmed M., Ibrahim, Alyaa Hatem, Tajuddeen, Nasir, Seibel, Jürgen, Bodem, Jochen, Geiger, Nina, Striffler, Kathrin, Bringmann, Gerhard, Abdelmohsen, Usama Ramadan
• Format: Article
• Language: English
• Subjects: Alkaloids; Antiviral Agents - pharmacology; COVID-19; Humans; Molecular Docking Simulation; Molecular Dynamics Simulation; Mpro; Naphthylisoquinolines; Natural products; Peptide Hydrolases - metabolism; Protease Inhibitors - chemistry; Research Paper; SARS-CoV-2; Steered molecular dynamics
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2023.115226

By combining docking and molecular dynamics simulations, we explored a library of 65 mostly axially chiral 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 consideration 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, that atropisomer-specifically inhibited the main protease (Mpro) activity of SARS-CoV-2 significantly in comparison to the reference covalent inhibitor GC376 (IC50 = 2.52 ± 0.14 and 0.88 ± 0.15 μM, respectively) and reduced viral growth by five orders of magnitude in vitro (EC50 = 4.23 ± 1.31 μM). To investigate the binding pathway and 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 site of the enzyme. The study presents naphthylisoquinoline alkaloids as a new class of potential anti-COVID-19 agents. [Display omitted] •Discovery of naphthylisoquinolines as a new class of potential anti-COVID-19 agents.•Screening of 65 axially chiral alkaloids for potential SARS CoV-2 Mpro inhibition.•Identification of korupensamine A as a new antiviral agent by computational methods.•Atropisomer-specific inhibition of SARS CoV-2 and its Mpro by korupensamine A.•Elucidation of the interaction of the korupensamine A Mpro complex using GaMD/MDS.