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

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. View Full-Tex

In silico evaluation of phenothiazine derivatives as trypanothione reductase inhibitors

Background: American trypanosomiasis is caused by parasite Trypanosoma cruzi, and it is considered a worldwide health problem. Current treatment consists of benznidazole and nifurtimox, which are not fully effective against both disease stages and have adverse effects. There is thus a need to find parasite-specific alternative treatments. Search of specific inhibitors of parasite-exclusive crucial enzymes is a known strategy. Trypanothione reductase (TR) enzyme is central in parasite’s redox system both for detoxification of reactive oxygen and nitrogen species as well as amino acid and nucleotide biosynthesis. Phenothiazine scaffold is known by pharmacologists as a very versatile structure and its derivatives have shown TR inhibition. A virtual screening of phenothiazine derivatives from PubChem database may permit finding potential TR inhibitors. Methodology: TR crystal was obtained from the PDB database (1GXF). A total of 100 phenothiazine derivatives complying with Lipinski’s rules were docked in TR active site using AutoDock Vina 1.1.2. Binding energy and interaction profiles, determined with PLIP (Protein-Ligand Interaction Profiler) server, were used to discriminate among derivatives. Results: Binding energy was found to be in the range of -10.9 to -6.1 kcal/mol compared to -8.8 kcal/mol of natural ligand trypanothione disulfide (TS2). Forty-two compounds showed a binding energy greater than or equal to natural ligand, top ten were determined interactions. Main interactions were found with residues important to TS2 binding: Phe396, Leu399, His461, Glu466 and Glu467. Conclusion: Best ranked compounds both by binding energy and interactions may be proposed as TR inhibitors and assayed in vitro to test effectivity