Banca de DEFESA: WEMENES JOSÉ LIMA SILVA
Uma banca de DEFESA de MESTRADO foi cadastrada pelo programa.STUDENT : WEMENES JOSÉ LIMA SILVA
DATE: 05/04/2023
TIME: 09:00
LOCAL: Sala 205 do Bloco Zeta do Campus de São Bernardo do Campo da Universidade Federal do ABC
TITLE:
In Silico Studies of the Free Energy of Binding of the Inhibitors of Kallikreins 5, 6, and 7
PAGES: 70
BIG AREA: Ciências Biológicas
AREA: Bioquímica
SUBÁREA: Química de Macromoléculas
SUMMARY:
The serine proteases KLK5, KLK7, and KLK6 play a crucial role in the pathogenesis of Netherton Syndrome (KLK5 and KLK7) and have been linked to neurodegenerative diseases (KLK6). Therefore, finding inhibitors against these enzymes could represent a potential therapeutic approach for treating these diseases and has attracted the attention of academic groups and the pharmaceutical industry. Structure-based virtual screening (SBVS) is a strategy that uses computational methods to identify new inhibitors. However, these methods are not yet accurate enough to calculate the free energy of binding (∆G), which limits their exclusive use in the optimization of hit into a lead compound. In this project, in silico studies were performed using more sophisticated computational methods such as molecular dynamics simulations followed by the calculation of the free energy of binding using methods such as GBSA, PBSA, and free energy perturbation (FEP). The results of these calculations were compared with experimental affinity values (pIC50) of inhibitors of KLK5, KLK6, and KLK7 to identify a computational protocol that can be used to guide the optimization of inhibitors of these enzymes. The correlation between the calculated (∆Gcal) and experimental (∆Gexp) free energy of binding was evaluated using the correlation coefficient (R2) and Kendall's coefficient (τ). The results using different approaches (docking, minimization, and molecular dynamics) showed that none of the evaluated protocols proved to be accurate for all collections of compounds. However, some protocols/methods showed promise in predicting the free energy of binding for a particular collection. Using distinct docking protocols, the R2 value ranged from 0.5 to 0.8 for four compound collections (K51, K52, K62 and K71). Also, the complex minimization followed by free energy calculation using the GBSA method produced satisfactory results only for the K51 (R2 = 0.7) and K61 (R2 = 0.9) collection. Unexpectedly, the free energy calculated from molecular dynamics simulations resulted in lower correlations than those obtained from docking. The Free Energy Perturbation (FEP) method applied to the collections of KLK6 inhibitors was accurate in predicting the ∆Gexp for the K61 (R2 0.8), K63 (R2 0.9), and K64 (R2 = 0.5) collections. Compared with the other computational methods, the FEP method was the only one that produced a satisfactory statistical correlation for the K63 collection.
COMMITTEE MEMBERS:
Presidente - Interno ao Programa - 003.058.336-50 - RENATO FERREIRA DE FREITAS - USP
Membro Titular - Examinador(a) Interno ao Programa - 1696841 - LUCIANO PUZER
Membro Titular - Examinador(a) Externo ao Programa - 149.405.258-05 - KATHIA MARIA HONORIO - USP
Membro Suplente - Examinador(a) Interno ao Programa - 2605490 - SERGIO DAISHI SASAKI
Membro Suplente - Examinador(a) Externo à Instituição - MARCELO BERGAMIN ZANI