Virtual Screening of Benzimidazole Derivatives as Potential Triose Phosphate Isomerase Inhibitors with Biological Activity against Leishmania mexicana

Abstract

Leishmania mexicana (L. mexicana) is a causal agent of cutaneous leishmaniasis (CL), a “Neglected disease”, for which the search for new drugs is a priority. Benzimidazole is a scaffold used to develop antiparasitic drugs; therefore, it is interesting molecule against L. mexicana. In this work, a ligand-based virtual screening (LBVS) of the ZINC15 database was performed. Subsequently, molecular docking was used to predict the compounds with potential binding at the dimer interface of triosephosphate isomerase (TIM) of L. mexicana (LmTIM). Compounds were selected on binding patterns, cost, and commercial availability for in vitro assays against L. mexicana blood promastigotes. The compounds were analyzed by molecular dynamics simulation on LmTIM and its homologous human TIM. Finally, the physicochemical and pharmacokinetic properties were determined in silico. A total of 175 molecules with docking scores between −10.8 and −9.0 Kcal/mol were obtained. Compound E2 showed the best leishmanicidal activity (IC50 = 4.04 µM) with a value similar to the reference drug pentamidine (IC50 = 2.23 µM). Molecular dynamics analysis predicted low affinity for human TIM. Furthermore, the pharmacokinetic and toxicological properties of the compounds were suitable for developing new leishmanicidal agents.

Triose Phosphate Isomerase Structure-Based Virtual Screening and In Vitro Biological Activity of Natural Products as Leishmania mexicana Inhibitors

“…Molecular dynamics simulation analysis was performed to predict the stability of the LmTIM protein in complex with the compounds B-3, S-3, S-7, S-8, and BTZ. The apo-LmTIM-free protein was also analyzed with these results, being comparable to those previously reported by our work group [45]. In general, compounds B-3 and S-8 in complex with LmTIM showed a more stable behavior than the complex with the control ligand (BTZ-LmTIM) due to their low RMSD and minimal differences in oscillations since they have been generally described in most molecular dynamics simulations with RMSD values < 2 Å with fluctuations between 0.7 and 9 Å, respectively [46][47][48].…”

GC‐MS, alpha‐amylase, and alpha‐glucosidase inhibition and molecular docking analysis of selected phytoconstituents of small wild date palm fruit (Phoenix pusilla)

“…The molecular docking studies were carryout by using the AutoDock Vina in Linux command mode (Vázquez‐Jiménez et al, 2023 ). Initially, a grid box was set according to the active site of the crystal structure of each protein mentioned in the above active site prediction section.…”

“…The molecular docking studies were carryout by using the AutoDock Vina in Linux command mode (Vázquez-Jiménez et al, 2023).…”

Synthesis of Antiprotozoal 2-(4-Alkyloxyphenyl)-Imidazolines and Imidazoles and Their Evaluation on Leishmania mexicana and Trypanosoma cruzi

“…In living cells, i8 is captured and reduced to its insoluble form (formazan, which is purple) by mitochondrial succinate dehydrogenase. The quantity of living cells is proportional to the amount of formazan produced [34]. In each well of a 96-well plate, 5 × 10 4 J774A.1 macrophages were added to a final volume of 100 µL in RPMI culture medium supplemented with 10% FBS, 1% ampicillin/streptomycin, and 1% MEM-NEAA.…”