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

[ Vol. 18 , Issue. 5 ]

Author(s):

Leonardo L.G. Ferreira, Rafaela S. Ferreira, David L. Palomino and Adriano D. Andricopulo*   Pages 397 - 405 ( 9 )

Abstract:


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.

Keywords:

Sleeping sickness, Human African trypanosomiasis, Drug discovery, Molecular docking, Molecular dynamics.

Affiliation:

Laboratorio de Quimica Medicinal e Computacional, Centro de Pesquisa e Inovacao em Biodiversidade e Farmacos, Instituto de Fisica de Sao Carlos, Universidade de Sao Paulo, Av. Joao Dagnone 1100, Sao Carlos – SP 13563-120, Departamento de Bioquimica e Imunologia, Universidade Federal de Minas Gerais, Av. Antonio Carlos 6627, Belo Horizonte – MG, 31270-901, Laboratorio de Quimica Medicinal e Computacional, Centro de Pesquisa e Inovacao em Biodiversidade e Farmacos, Instituto de Fisica de Sao Carlos, Universidade de Sao Paulo, Av. Joao Dagnone 1100, Sao Carlos – SP 13563-120, Laboratorio de Quimica Medicinal e Computacional, Centro de Pesquisa e Inovacao em Biodiversidade e Farmacos, Instituto de Fisica de Sao Carlos, Universidade de Sao Paulo, Av. Joao Dagnone 1100, Sao Carlos – SP 13563-120

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