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Hit-to-lead optimization of Trypanosoma cruzi dihydroorotate dehydrogenase inhibitors

Grant number: 12/01777-6
Support type:Scholarships abroad - Research Internship - Post-doctor
Effective date (Start): March 15, 2012
Effective date (End): March 14, 2013
Field of knowledge:Physical Sciences and Mathematics - Chemistry
Principal Investigator:Carlos Alberto Montanari
Grantee:Josmar Rodrigues da Rocha
Supervisor abroad: Kiyoshi Kita
Home Institution: Instituto de Química de São Carlos (IQSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil
Local de pesquisa : University of Tokyo, Japan  
Associated to the scholarship:10/20021-4 - Trypanosoma cruzi dihydroorotate dehydrogenase hit-to-lead optimisation, BP.PD

Abstract

In the last few years, our research group has been focusing on the design of inhibitors targeting the enzyme dihydroorotate dehydrogenase from Trypanosoma Cruzi (TcDHODH). In order to accomplish this, we have applied computational and biochemical methods to investigate structural and catalytic mechanism properties which might be useful to the identification of small molecules able to modulate the TcDHODH activity. In a first stage, a novel exportable pocket (S2 site) was identified and validated through the Isothermal Titration Calorimetric assays of a series of substrate analogs, from which three of these exhibited affinity by the enzyme at low micromolar range. Then, a new series of compounds was designed to occupy S2 site. The in vitro evaluation of those compounds against the TcDHODH enzyme resulted in the identification of other eleven ligands, of which the most potent exhibited affinity for the enzyme at the concentration of 124 nM. Furthermore, the most potent hits have remarkable Ligand Efficiency (~0.5 kcal mol-1 atom-1) and can be considered as fragment-like compounds with excellent potential for future development as therapeutic agent. Thus, in this study we propose the application of X-ray crystallography as a mean to support our previous results through the investigation the mode of binding (MOB) of the identified hits, since these information are able to provide the necessary insights to allow us the identification of key functionalities to be added to the next generation of hits so that we can evolve to more a more potent and diverse series of compounds able to fulfill appropriate profile as leads for next steps in the drug discovery pipeline. (AU)