Cruzain inhibitors: efforts made, current leads and a structural outlook of new hits

• Published in: Drug discovery today 2015-07, Vol.20 (7), p.890-898
• Main Authors: Martinez-Mayorga, Karina, Byler, Kendall G., Ramirez-Hernandez, Ariadna I., Terrazas-Alvares, Diana E.
• Format: Article
• Language: English
• Subjects: Animals; Chagas Cardiomyopathy - drug therapy; Chagas Cardiomyopathy - parasitology; Computer-Aided Design; Cysteine Endopeptidases - chemistry; Cysteine Endopeptidases - metabolism; Drug Design; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; High-Throughput Screening Assays; Humans; Ligands; Molecular Docking Simulation; Molecular Structure; Protozoan Proteins - antagonists & inhibitors; Protozoan Proteins - chemistry; Protozoan Proteins - metabolism; Structure-Activity Relationship; Trypanocidal Agents - chemistry; Trypanocidal Agents - pharmacology; Trypanosoma brucei brucei - drug effects; Trypanosoma brucei brucei - enzymology; Trypanosoma cruzi - drug effects; Trypanosoma cruzi - enzymology; Trypanosomiasis, African - drug therapy; Trypanosomiasis, African - parasitology
• ISSN: 1359-6446; 1878-5832
• DOI: 10.1016/j.drudis.2015.02.004

•SAR and docking studies should be interpreted considering the possibility of aggregation.•SAR does not necessarily imply a specific binding interaction.•Neutral molecules are preferable as cysteine protease inhibitors.•Leads obtained from strategies such as traditional medicinal chemistry or modeling-based inhibitors could benefit with the knowledge accumulated for the development of inhibitors such as odanacatib. Human African trypanosomiasis and Chagas disease are the main causes of heart failure in developing countries. The disadvantages of current therapy include: undesirable side-effects, resistance, lack of efficacy on late-stage disease and lack of pediatric formulations. Efforts to find new compound hits have spanned SAR studies to very high-throughput and virtual screens and drug repurposing. The integrated analysis of these strategies on the discovery of anti-Chagas agents is timely. This work accounts for the progress on the development of cruzain inhibitors following these avenues, with emphasis on structural aspects of the ligand–cruzain recognition process.