Molecular modeling and structure-activity relationships for a series of benzimidazole derivatives as cruzain inhibitors.
AIM
Chagas disease is endemic in Latin America and no effective treatment is available. Efforts in drug research have focused on several enzymes from Trypanosoma cruzi, among which cruzain is a validated pharmacological target.


METHODOLOGY
Chemometric analyses were performed on the data set using the hologram quantitative structure-activity relationship, comparative molecular field analysis and comparative molecular similarity index analysis methods. Docking simulations were executed using the crystallographic structure of cruzain in complex with a benzimidazole inhibitor. The top-scoring enzyme-inhibitor complexes were selected for the development of the 3D quantitative structure-activity relationship (QSAR) models and to assess the inhibitor binding modes and intermolecular interactions.


RESULTS
Benzimidazole derivatives as cruzain inhibitors were used in molecular docking and QSAR studies. Significant statistical indicators were obtained, and the best models demonstrated high predictive ability for an external test set (r 2pred = 0.65, 0.94 and 0.82 for hologram QSAR, comparative molecular field analysis and comparative molecular similarity index analysis, respectively). Additionally, the graphical information of the chemometric analyses demonstrated substantial complementarity with the enzyme-binding site.


CONCLUSION
These results demonstrate the relevance of the QSAR models to guide the design of structurally related benzimidazole derivatives with improved potency.
['Pauli|Ivani|I|', 'Ferreira|Leonardo G|LG|', 'de Souza|Mariana L|ML|', 'Oliva|Glaucius|G|', 'Ferreira|Rafaela S|RS|', 'Dessoy|Marco A|MA|', 'Slafer|Brian W|BW|', 'Dias|Luiz C|LC|', 'Andricopulo|Adriano D|AD|']
D001562:Benzimidazoles D001665:Binding Sites D014355:Chagas Disease D003546:Cysteine Endopeptidases D015853:Cysteine Proteinase Inhibitors D055808:Drug Discovery D006801:Humans D008958:Models, Molecular D062105:Molecular Docking Simulation D015394:Molecular Structure D011485:Protein Binding D015800:Protozoan Proteins D021281:Quantitative Structure-Activity Relationship D013020:South America D014344:Trypanocidal Agents D014349:Trypanosoma cruzi
molecular modeling Trypanosoma cruzi QSAR CoMFA CoMSIA HQSAR LBDD SBDD