Ligand-Based Virtual Screening and Molecular Docking of Benzimidazoles as Potential Inhibitors of Triosephosphate Isomerase Identified New Trypanocidal Agents

• Published in: International journal of molecular sciences 2022-09, Vol.23 (17), p.10047
• Main Authors: Vázquez-Jiménez, Lenci K, Juárez-Saldivar, Alfredo, Gómez-Escobedo, Rogelio, Delgado-Maldonado, Timoteo, Méndez-Álvarez, Domingo, Palos, Isidro, Bandyopadhyay, Debasish, Gaona-Lopez, Carlos, Ortiz-Pérez, Eyra, Nogueda-Torres, Benjamín, Ramírez-Moreno, Esther, Rivera, Gildardo
• Format: Article
• Language: English
• Subjects: Adenosine triphosphate; Amino acids; Animals; ATP; Benzimidazoles; Benzimidazoles - chemistry; Benzimidazoles - pharmacology; Binding sites; Chagas disease; Drug development; Glycolysis; Humans; inhibitors; Ligands; Mammals - metabolism; Metabolic pathways; Molecular docking; Molecular Docking Simulation; Molecular dynamics; Pharmacokinetics; Pharmacology; Proteins; Protozoa; Simulation; Triose-phosphate isomerase; Triose-Phosphate Isomerase - metabolism; triosephosphate isomerase; Trypanocidal Agents - chemistry; Trypanocidal Agents - pharmacology; Trypanosoma cruzi; Trypanosoma cruzi - metabolism; Trypomastigotes
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms231710047

( ) is a parasite that affects humans and other mammals. depends on glycolysis as a source of adenosine triphosphate (ATP) supply, and triosephosphate isomerase (TIM) plays a key role in this metabolic pathway. This enzyme is an attractive target for the design of new trypanocidal drugs. In this study, a ligand-based virtual screening (LBVS) from the ZINC15 database using benzimidazole as a scaffold was accomplished. Later, a molecular docking on the interface of TIM ( TIM) was performed and the compounds were grouped by interaction profiles. Subsequently, a selection of compounds was made based on cost and availability for in vitro evaluation against blood trypomastigotes. Finally, the compounds were analyzed by molecular dynamics simulation, and physicochemical and pharmacokinetic properties were determined using SwissADME software. A total of 1604 molecules were obtained as potential TIM inhibitors. BP2 and BP5 showed trypanocidal activity with half-maximal lytic concentration (LC ) values of 155.86 and 226.30 µM, respectively. Molecular docking and molecular dynamics simulation analyzes showed a favorable docking score of BP5 compound on TIM. Additionally, BP5 showed a low docking score (-5.9 Kcal/mol) on human TIM compared to the control ligand (-7.2 Kcal/mol). Both compounds BP2 and BP5 showed good physicochemical and pharmacokinetic properties as new anti- agents.