Ligand-induced conformational selection predicts the selectivity of cysteine protease inhibitors

Autor(es)

Sartori, Geraldo Rodrigues ^[1] ; Leitao, Andrei ^[1] ; Montanari, Carlos A. ^[1] ; Laughton, Charles A. ^{[2, 3]}

Afiliação do(s) autor(es)

^[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

• Tipo de documento: Artigo Científico
• Fonte: PLoS One; v. 14, n. 12 DEC 19 2019.
• Citações Web of Science: 1

Resumo

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)

• Processo FAPESP: 13/18009-4 - Planejamento, síntese e atividade tripanossomicida de inibidores covalentes reversíveis da enzima cruzaína
• Beneficiário: Carlos Alberto Montanari
• Modalidade de apoio: Auxílio à Pesquisa - Temático