Design of inhibitors of kallikreins 5, 6, and 7 using computational methods and fragment-based approaches

• Grant number: 18/11011-7
• Support Opportunities: Research Grants - Young Investigators Grants
• Start date: June 01, 2019
• End date: May 31, 2025
• Field of knowledge: Physical Sciences and Mathematics - Chemistry
• Principal Investigator: Renato Ferreira de Freitas
• Grantee: Renato Ferreira de Freitas
• Host Institution: Centro de Ciências Naturais e Humanas (CCNH). Universidade Federal do ABC (UFABC). Ministério da Educação (Brasil). Santo André , SP, Brazil
• Associated researchers: Luciano Puzer ; Rodrigo Luiz Oliveira Rodrigues Cunha
• Associated scholarship(s): 21/04450-7 - In silico studies of the free energy of binding of kallikrein inhibitors, BP.MS; 19/08603-2 - Design of inhibitors of kallikreins 5, 6, and 7 using computational methods and fragment-based approaches, BP.JP

Abstract

The enzymes KLK5, KLK6, and KLK7 (designated KLK5-KLK7 hereinafter) are serine proteases and belong to the kallikrein family. These enzymes are involved in important physiological mechanisms such as skin desquamation and neural development. In addition to its important role in normal cell function, evidence shows that the deregulation of KLK5-KLK7expression or the excessive increase of their proteolytic activity are associated with several diseases such as cancer, Nether ton syndrome and multiple sclerosis. Accordingly, the inhibition of these enzymes may represent novel targets for the treatment of such diseases. However, the absence of potent, selective and active inhibitors in cellular and animal models makes it difficult to validate KLK5-KLK7 as therapeutic targets. So, this project proposes the combined use of computational and experimental methods for the identification and optimization of KLK5-KLK7inhibitors that can be used to investigate the relevance of these enzymes in different diseases. The availability of the X-ray structures of KLK5-KLK7 complexes with small molecules as well as the chemical structure of a few inhibitors will allow the use of receptor and ligand based virtual screening methods in order to select a small number compounds that are highly likely to be active in the experimental assays. In combination with computational methods, this project will also apply the fragment-based (compounds with molecular weight between 150 and250 Da) screening to identify new inhibitors of the KLK5-KLK7 enzymes. This is a validated strategy for the identification of ligands and allows to explore the chemical space more efficiently than the screening of collections of compounds with drug-like properties. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

DE FREITAS, RENATO FERREIRA; IVANOCHKO, DANTON; SCHAPIRA, MATTHIEU. Methyltransferase Inhibitors: Competing with, or Exploiting the Bound Cofactor. Molecules, v. 24, n. 24, DEC 2019. (18/11011-7, 19/08603-2)

LIMA SILVA, WEMENES JOSE; DE FREITAS, RENATO FERREIRA. Assessing the performance of docking, FEP, and MM/GBSA methods on a series of KLK6 inhibitors. Journal of Computer-Aided Molecular Design, v. 37, n. 9, p. 12-pg., 2023-06-28. (18/11011-7, 19/08603-2, 21/04450-7)