Abstract
To establish a procedure for screening compounds that inhibit ligand–receptor binding, we used a multidimensional virtual- system coupled molecular dynamics (mD-VcMD), which is a generalized ensemble method developed by ourselves recently. In this sampling method, the compound was put at a distant point from the receptor in the initial conformation of simulation. Both the receptor and the compound were fully flexible in explicit solvent during sampling. The mD-VcMD produced a free-energy landscape of the compound–receptor binding, where a probability of existence was assigned to each sampled conformation. We examined four compounds binding to the papain-like protease (PLpro) of SARS-CoV-2. The resultant free-energy landscapes were funnel-like for all compounds. The probability assigned to the free-energy basins showed good correlation with the measured association constants. Furthermore, structural clustering identified binding modes of two types existing in the free-energy basin. The probability assigned to the binding modes showed good correlation with the measured enzyme-inhibitory. These results suggest that this proposed procedure is useful to select a candidate compound (inhibitor) from examined compounds.