| Full text | |
| Author(s): |
Sartori, Geraldo Rodrigues
[1]
;
Leitao, Andrei
[1]
;
Montanari, Carlos A.
[1]
;
Laughton, Charles A.
[2, 3]
Total Authors: 4
|
| Affiliation: | [1] Univ Sao Paulo, Grp Quim Med IQSC USP, Inst Quim Sao Carlos, Sao Carlos, SP - Brazil
[2] Univ Nottingham, Sch Pharm, Nottingham - England
[3] Univ Nottingham, Ctr Biomol Sci, Nottingham - England
Total Affiliations: 3
|
| Document type: | Journal article |
| Source: | PLoS One; v. 14, n. 12 DEC 19 2019. |
| Web of Science Citations: | 1 |
| Abstract | |
Cruzain, a cysteine protease of Trypanosoma cruzi, is a validated target for the treatment of Chagas disease. Due to its high similarity in three-dimensional structure with human cathepsins and their sequence identity above 70% in the active site regions, identifying potent but selective cruzain inhibitors with low side effects on the host organism represents a significant challenge. Here a panel of nitrile ligands with varying potencies against cathepsin K, cathepsin L and cruzain, are studied by molecular dynamics simulations as both non-covalent and covalent complexes. Principal component analysis (PCA), identifies and quantifies patterns of ligand-induced conformational selection that enable the construction of a decision tree which can predict with high confidence a low-nanomolar inhibitor of each of three proteins, and determine the selectivity for one against others. (AU) | |
| FAPESP's process: | 13/18009-4 - Molecular Design, Synthesis and Trypanocidal Activity of Cruzain Reversible Covalent Inhibitors |
| Grantee: | Carlos Alberto Montanari |
| Support Opportunities: | Research Projects - Thematic Grants |