Docking and Pharmacokinetic studies on derivatives diaryl sulfide conjugated to mepacrine against Trypanosoma cruzi Trypanothione Reductase

Trypanosoma cruzi, the causative of (until) untreatable Chagas disease, mainly for its chronic phase1, has a Trypanothione Redutase (TcTR), a validated target2. 48 diaryl sulfide conjugated to mepacrine tested against TcTR3 were studied by docking. Their pharmacokinetic properties4 presented: good intestinal absorption (≥ 89%), poor CNS penetration (Log PS ≤ -2); P-glycoprotein inhibition, except MOL40; do not inhibit the hERG channels. Thus, we docked them into TcTR using Autodock v.4.25 aiming to study their inhibitory mechanism. MOL39 and MOL5 (best energy values, respectively: -13.61 and -13.08 kcal/mol) interacted with hydrophobic patch (TYR-111, MET-114, LEU-18, TRP-22) and the Z site (LEU-399, PRO-398, PHE-396). MOL30 and MOL40 (lower energies) made only few hydrogen bonding interactions with GLU-466, GLU-467 and THR-66. Thus, we concluded that docking help us to explain the inhibitory behavior at TcTR and pharmacokinetics data could aid the selection of lower toxic derivatives for developing new anti-Chagas compounds.