Análise estrutural e desenvolvimento de estratégias de inibição para a proteína KSRP em Cinetoplastídeos

Abstract

Neglected diseases caused by kinetoplastids, such as Chagas disease and leishmaniasis, affect millions of people globally. Current treatments are limited by low efficacy, toxicity, and emerging resistance, making the search for novel therapeutic targets a critical priority. The Kinetoplastid-Specific Ribosomal Protein (KSRP) from Trypanosoma cruzi emerges as a promising target due to its exclusivity to this parasite group and its essential role in ribosomal integrity. However, the molecular basis of its interactions and its potential for inhibition remain largely unexplored. To address this gap, this dissertation proposes and applies computational methods to identify and characterize interaction sites on KSRP. Our strategy integrated structural data from the T. cruzi KSRP (PDB ID: 5OPT, chain h) with databases, including Propedia, using a comprehensive suite of bioinformatics tools such as molecular docking (HDOCK, HPEPDOCK, AlphaFold3), analysis of interatomic contacts (PRODIGY), solvent accessibility (NACCESS), and residue flexibility (CABS-flex 2.0). These analyses led to the identification of 47 functionally relevant residues strategically distributed across the four KSRP domains (RRM1: 22; LINKER: 10; RRM2: 11; C-TERM: 4). These residues were consistently found at contact interfaces and in regions of high accessibility and structural flexibility. Notably, our results suggest that peptide binding could induce allosteric conformational changes in KSRP, a valuable insight for inhibitor design. By mapping these critical sites, this work provides a structural foundation for the rational design of peptides aimed at disrupting KSRP function, potentially leading to parasite death. Furthermore, the proposed methodology is applicable to the characterization of other target proteins, contributing to innovation in the fight against neglected diseases and expanding the prospects for the development of new therapies.