Assessment of the inhibition mechanism of phenoxymethylketones against Cruzipain by hybrid QM/MM-MD simulation

CERUTTI, JUAN P.; DEHAEN, W.; ROITBERG, A.; QUEVEDO, M.A.

Congreso; Reunión Internacional de Ciencias Farmacéuticas (RiCiFa-2021); 2021

Cruzipain (CZP) is the main cysteine protease of T. cruzi, the causative agent of Chagas disease, and thus, a therapeutic target of interest for rational drug design. In this work, the inhibition mechanism of the most potent reported phenoxymethylketone (PMK) derivative was evaluated by hybrid quantum mechanics/molecular mechanics molecular dynamics (QM/MM-MD) studies. Three feasible inhibition pathways were explored against both monomeric and homodimeric CZP. QM/MM-MD simulations were performed on the Tupac supercomputer (Argentina), employing the Amber20 package. The SCC-DFTB semiempirical method and the ff14SB and TIP3P force fields were applied for the QM and classic regions, respectively.A two-step inhibition pathway was found to be the most energetically favourable, involving theformation of a tetrahedral thiohemiketal intermediate, followed by a rearrangement yielding the finalthioether adduct with tetrafluorophenol displacement. An alternative stepwise mechanism via aprotonated thiohemiketal intermediate and a concerted one showed less or non-feasibility of occurrence.Additionally, lower activation energies were observed for the reactions entailing the homodimer,suggesting potential homodimeric CZP activity. Overall, these findings aim to improve theunderstanding of the molecular mechanism of PMK derivatives against CZP, paving the way for thedesign of new inhibitors for the effective treatment of Chagas disease.