Molecular description of α-keto-based inhibitors of cruzain with activity against Chagas disease combining 3D-QSAR studies and molecular dynamics.

Abstract

In this work, a group of α-keto-based inhibitors of the cruzain enzyme with anti-chagas activity was selected for a three-dimensional quantitative structure-activity relationship study (3D-QSAR) combined with molecular dynamics (MD). Firstly, statistical models based on Partial Least Square (PLS) regression were developed employing comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) descriptors. Validation parameters (q2 and r2 )for the models were, respectively, 0.910 and 0.997 (CoMFA) and 0.913 and 0.992 (CoMSIA). In addition, external validation for the models using a test group revealed r2pred  = 0.728 (CoMFA) and 0.971 (CoMSIA). The most relevant aspect in this study was the generation of molecular fields in both favorable and unfavorable regions based on the models developed. These fields are important to interpret modifications necessary to enhance the biological activities of the inhibitors. This analysis was restricted considering the inhibitors in a fixed conformation, not interacting with their target, the cruzain enzyme. Then, MD was employed taking into account important variables such as time and temperature. MD helped describe the behavior of the inhibitors and their properties showed similar results as those generated by QSAR-3D study.

• Authors: Ádria P B Saraiva, Ricardo M Miranda, Renan P P Valente, Jéssica O Araújo, Rutelene N B Souza, Clauber H S Costa, Amanda R S Oliveira, Michell O Almeida, Antonio F Figueiredo, João E V Ferreira, Cláudio Nahum Alves, Kathia M Honorio
• Journal: Chemical biology & drug design (Chem Biol Drug Des) Vol. 92 Issue 2 Pg. 1475-1487 (08 2018) ISSN: 1747-0285 [Electronic] England
• PMID: 29682904 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 John Wiley & Sons A/S.

Chemical References

• Protozoan Proteins
• Cysteine Endopeptidases
• cruzipain

Topics

• Binding Sites
• Catalytic Domain
• Chagas Disease (drug therapy, pathology)
• Cysteine Endopeptidases (metabolism)
• Humans
• Least-Squares Analysis
• Molecular Dynamics Simulation
• Protozoan Proteins (antagonists & inhibitors, metabolism)
• Quantitative Structure-Activity Relationship