Structure-Based Virtual Screening and Biochemical Evaluation for the Identification of Novel Trypanosoma brucei Aldolase Inhibitors

Autor(es)

Ferreira, Leonardo L. G. ^[1] ; Ferreira, Rafaela S. ^[2] ; Palomino, David L. ^[1] ; Andricopulo, Adriano D. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Inst Fis Sao Carlos, Ctr Pesquisa & Inovacao Biodiversidade & Farm, Lab Quim Med & Comp, Ave Joao Dagnone 1100, BR-13563120 Sao Carlos, SP - Brazil

^[2] Univ Fed Minas Gerais, Dept Bioquim & Imunol, Ave Antonio Carlos 6627, BR-31270901 Belo Horizonte, MG - Brazil

• Tipo de documento: Artigo de Revisão
• Fonte: CURRENT TOPICS IN MEDICINAL CHEMISTRY; v. 18, n. 5, p. 397-405, 2018.
• Citações Web of Science: 3

Resumo

Introduction: The glycolytic enzyme fructose-1,6-bisphosphate aldolase is a validated molecular target in human African trypanosomiasis (HAT) drug discovery, a neglected tropical disease (NTD) caused by the protozoan Trypanosoma brucei. Herein, a structure-based virtual screening (SBVS) approach to the identification of novel T. brucei aldolase inhibitors is described. Distinct molecular docking algorithms were used to screen more than 500,000 compounds against the X-ray structure of the enzyme. This SBVS strategy led to the selection of a series of molecules which were evaluated for their activity on recombinant T. brucei aldolase. The effort led to the discovery of structurally new ligands able to inhibit the catalytic activity of the enzyme. Results: The predicted binding conformations were additionally investigated in molecular dynamics simulations, which provided useful insights into the enzyme-inhibitor intermolecular interactions. Conclusion: The molecular modeling results along with the enzyme inhibition data generated practical knowledge to be explored in further structure-based drug design efforts in HAT drug discovery. (AU)

• Processo FAPESP: 13/07600-3 - CIBFar - Centro de Inovação em Biodiversidade e Fármacos
• Beneficiário: Glaucius Oliva
• Linha de fomento: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 13/25658-9 - Planejamento e desenvolvimento de candidatos a fármacos para a Doença de Chagas
• Beneficiário: Leonardo Luiz Gomes Ferreira
• Linha de fomento: Bolsas no Brasil - Pós-Doutorado