Molecular docking and dynamic simulations of quinoxaline 1,4-di-N-oxide as inhibitors for targets from Trypanosoma cruzi, Trichomonas vaginalis, and Fasciola hepatica.

Context: Quinoxaline 1,4-di-N-oxide is a scaffold with a wide array of biological activities, particularly its use to develop new antiparasitic agents. Recently, these compounds have been described as trypanothione reductase (TR), triosephosphate isomerase (TIM), and cathepsin-L (CatL) inhibitors from Trypanosoma cruzi, Trichomonas vaginalis, and Fasciola hepatica, respectively.

Methods: Therefore, the main objective of this work was to analyze quinoxaline 1,4-di-N-oxide derivatives of two databases (ZINC15 and PubChem) and literature by molecular docking, dynamic simulation and complemented by MMPBSA, and contact analysis of molecular dynamics' trajectory on the active site of the enzymes to know their potential effect inhibitory. Interestingly, compounds Lit_C777 and Zn_C38 show preference as potential TcTR inhibitors over HsGR, with favorable energy contributions from residues including Pro398 and Leu399 from Z-site, Glu467 from γ-Glu site, and His461, part of the catalytic triad. Compound Lit_C208 shows potential selective inhibition against TvTIM over HsTIM, with favorable energy contributions toward TvTIM catalytic dyad, but away from HsTIM catalytic dyad. Compound Lit_C388 was most stable in FhCatL with a higher calculated binding energy by MMPBSA analysis than HsCatL, though not interacting with catalytic dyad, holding favorable energy contribution from residues oriented at FhCatL catalytic dyad. Therefore, these kinds of compounds are good candidates to continue researching and confirming their activity through in vitro studies as new selective antiparasitic agents.