Interaction of panduratin A and derivatives with the SARS-CoV-2 main protease (m^pro): a molecular docking study

Panduratin A (Pa-A) is a prenylated cyclohexenyl chalcone isolated from the rhizomes of the medicinal and culinary plant Boesenbergia rotunda (L.) Mansf., commonly called fingerroots. Both an ethanolic plant extract and Pa-A have shown a marked antiviral activity against the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), responsible for the COVID-19 pandemic disease. Pa-A functions as a protease inhibitor inhibiting infection of human cells by the virus. We have modeled the interaction of Pa-A, and 26 panduratin analogues with the main protease (M^pro) of SARS-CoV-2 using molecular docking. The natural product 4-hydroxypanduratin showed a higher M^pro binding capacity than Pa-A and isopanduratin A. The interaction with M^Pro of all known panduratin derivatives (Pa-A to Pa-Y) have been compared, together with more than 60 reference products. Three compounds emerged as potential robust M^Pro binders: Pa-R, Pa-V, Pa-S, with a binding capacity significantly higher than 4-OH-Pa-A and Pa-A. The empirical energy of interaction (ΔE) calculated with the best compound in the panduratin series, Pa-R bound to M^pro, surpassed that measured with the top reference protease inhibitors such a ruprintrivir, lufotrelvir, and glecaprevir. Structure-binding relationships are discussed. Compounds with a flavanone moiety (PA-R/S) are the best binders, better than those with a chromene unit (Pa-F/G). The extended molecules (such as Pa-V) exhibit good M^pro binding, but the dimeric compound Pa-Y is too long and protrudes outside the binding cavity. The work provides novel ideas to guide the design of new molecules interacting with M^pro.Communicated by Ramaswamy H. Sarma.