Trypanosoma cruzi Sirtuin 2 as a Relevant Druggable Target: New Inhibitors Developed by Computer-Aided Drug Design

Author(s):Show less -

Ferreira, Glaucio Monteiro ; Kronenberger, Thales ; Maltarollo, Vinicius Goncalves ; Poso, Antti ; Gatti, Fernando de Moura ; Almeida, Vitor Medeiros ; Marana, Sandro Roberto ; Lopes, Carla Duque ; Tezuka, Daiane Yukie ; de Albuquerque, Sergio ; Emery, Flavio da Silva ; Trossini, Gustavo Henrique Goulart

• Document type: Journal article
• Source: PHARMACEUTICALS; v. 16, n. 3, p. 14-pg., 2023-03-01.

Abstract

Trypanosoma cruzi, the etiological agent of Chagas disease, relies on finely coordinated epigenetic regulation during the transition between hosts. Herein we targeted the silent information regulator 2 (Sir2) enzyme, a NAD(+)-dependent class III histone deacetylase, to interfere with the parasites' cell cycle. A combination of molecular modelling with on-target experimental validation was used to discover new inhibitors from commercially available compound libraries. We selected six inhibitors from the virtual screening, which were validated on the recombinant Sir2 enzyme. The most potent inhibitor (CDMS-01, IC50 = 40 mu M) was chosen as a potential lead compound. (AU)

• FAPESP's process: 16/22365-9 - Enzyme structural network and dynamics
• Grantee: Sandro Roberto Marana
• Support Opportunities: Regular Research Grants
• FAPESP's process: 19/06172-4 - Post-doctorate fellow in search of new drugs against Hypercholesterolemia, based on specific genetic and epigenetic markers of the Brazilian population
• Grantee: Glaucio Monteiro Ferreira
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 17/25543-8 - Medicinal Chemistry strategies (LBDD and SBDD) in the search of tripanomatides sirtuin 2 inhibitors
• Grantee: Gustavo Henrique Goulart Trossini
• Support Opportunities: Regular Research Grants