Exploring Sirtuin 2 Inhibitors as Anti-Leishmanial Therapy Candidates: A Virtual Screening Approach

• Ano de defesa: 2025
• Autor(a) principal: Jesus, Jullyane Gabryelly de
• Tipo de documento: Dissertação
• Tipo de acesso: Acesso aberto
• Idioma: eng
• Instituição de defesa: Biblioteca Digitais de Teses e Dissertações da USP
• Palavras-chave em Português: Doenças Tropicais negligenciadas; Leishmania; SIR2RP1; Sirtuína 2; Triagem virtual
• Link de acesso: https://www.teses.usp.br/teses/disponiveis/9/9143/tde-06022026-145313/

Leishmaniasis is a neglected tropical disease that causes significant morbidity and mortality worldwide. Current treatments are limited by toxicity, high cost, and low efficacy, reinforcing the need for safer and more selective therapeutic alternatives. Sirtuin 2 (SIR2RP1), an NAD+-dependent deacetylase, plays essential roles in the physiology and survival of protozoa of the genus Leishmania, making it a promising target for drug development. This study focuses on identifying and evaluating potential inhibitors of Leishmania SIR2RP1 using in silico methods. Known sirtuin inhibitors are systematically analyzed based on their selectivity indices (SI), therapeutic indices (TI), and drug-likeness profiles to prioritize the most promising candidates. Through this comparative analysis, N-(2-Fluorophenyl)nicotinamide (NmoF) emerges as the reference compound due to its outstanding selectivity for Leishmania sirtuins and favorable molecular properties. Based on this prioritization, a ligand-based virtual screening (LBVS) of 460,160 compounds from the Enamine Hit Locator Library (HLL-460) is carried out using ROCS/VROCS to identify novel compounds that are structurally and electrostatically similar to NmoF. This targeted screening identifies 7 new molecules with high selectivity and potential inhibitory activity against Leishmania SIR2RP1. Hits are evaluated for their ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties to assess pharmacokinetic and safety profiles. Overall, this study aims to propose new candidate compounds for development as selective anti-Leishmania agents, contributing to the search for safer and more effective treatments against leishmaniasis.