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

Abstract

Trypanosoma cruzi (T. cruzi) is a parasite that affects humans and other mammals. T. cruzi 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 T. cruzi TIM (TcTIM) 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 TcTIM inhibitors. BP2 and BP5 showed trypanocidal activity with half-maximal lytic concentration (LC50) 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 TcTIM. 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-T. cruzi agents.

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

“…In general, the compounds P9 , E2 , and the control ligand in complex with Lm TIM had a fluctuating behavior that suggests a change in the initial binding position [ 38 , 39 ]. The complex with the lowest RMSD and minimal differences between oscillations has been described as the most stable [ 40 ].…”

Stylopine: A potential natural metabolite to block vascular endothelial growth factor receptor 2 (VEGFR2) in osteosarcoma therapy

“… Shreevatsa et al, 2021 predicted that orientin has better binding affinity towards NAD(P)H:quinone acceptor oxidoreductase-1 (NQO1) for anticancer activity using PyRx virtual screening tool ( Shreevatsa et al, 2021 ). Vázquez-Jiménez et al, 2022 conducted ligand-based virtual screening using PyRx tool for predicting binding affinity of various benzimidazoles targeting as triosephosphate isomerase inhibitor ( Vázquez-Jiménez et al, 2022 ).…”

State-of-the-art Review on the Antiparasitic Activity of Benzimidazolebased Derivatives: Facing Malaria, Leishmaniasis, and Trypanosomiasis

“…Several inhibitors belonging to benzothiazole [ 104 , 105 ], benzoxazole [ 106 ], and benzimidazole [ 107 ] chemical classes exhibited the ability to target the TIM enzyme. In this field, Vázquez-Jiménez et al [ 108 ] detected novel benzimidazole compounds capable of interacting with the TcTIM interface region by performing a ligand-based virtual screening (LBVS) from the ZINC15 database. From a total of 67,141 benzimidazole-containing compounds, 1604 compounds were selected because of their binding energy values between -10.6 and -8.9 Kcal/mol and adherence to Lipinski rules.…”

“…Finally, docking calculations unravelled a preferential selectivity of 18b for the trypanosomal isoform of the glycolytic enzyme, TcTIM (DGbind= -10.2 Kcal/mol), over the human isoform (HsTIM: DGbind= -5.9 Kcal/mol) [ 108 ].…”