A pharmacophore-based virtual screening approach for the discovery of Trypanosoma cruzi GAPDH inhibitors

Author(s)

Maluf, Fernando V. ^[1] ; Andricopulo, Adriano D. ^[1] ; Oliva, Glaucius ^[1] ; Guido, Rafael V. C. ^[1]

Affiliation

^[1] Univ Sao Paulo, Inst Fis Sao Carlos, Ctr Inovacao Biodiversidade & Farmacos, Lab Quim Med & Computac, BR-13563120 Sao Carlos, SP - Brazil

• Document type: Journal article
• Source: Future Medicinal Chemistry; v. 5, n. 17, p. 2019-2035, NOV 2013.
• Web of Science Citations: 17

Abstract

Background: Chagas disease is a major cause of morbidity and death for millions of people in Latin America. The drugs currently available exhibit poor efficacy and severe side effects. Therefore, there is an urgent need for new, safe and effective drugs against Chagas disease. The vital dependence on glycolysis as energy source makes the glycolytic enzymes of Trypanosoma cruzi, the causative agent of Chagas disease, attractive targets for drug design. In this work, glyceraldehyde-3-phosphate dehydrogenase from T. cruzi (TcGAPDH) was employed as molecular target for the discovery of new inhibitors as hits. Results: Integrated protein-based pharmacophore and structure-based virtual screening approaches resulted in the identification of three hits from three chemical classes with moderate inhibitory activity against TcGAPDH. The inhibitors showed IC50 values in the high micromolar range. Conclusion: The new chemotypes are attractive molecules for future medicinal chemistry efforts aimed at developing new lead compounds for Chagas disease. (AU)

• FAPESP's process: 13/07600-3 - CIBFar - Center for Innovation in Biodiversity and Drug Discovery
• Grantee: Glaucius Oliva
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC