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Hot spots identification and molecular fragment screening as innovative approaches to development Leishmania major diidroorotate dehydrogenase inhibitors

Grant number: 19/25532-1
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): April 01, 2021
Effective date (End): March 31, 2023
Field of knowledge:Biological Sciences - Biophysics - Molecular Biophysics
Principal researcher:Maria Cristina Nonato
Grantee:Thamires Quadros Froes
Home Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Although affecting more than 1 billion people and causing 35.000 deaths/day worldwide, the Neglected Tropical Diseases (NTD) are still characterized by low investment from both private and public sectors towards the development of new therapies and methods to control these ailments. Among NTDs, Cutaneous Leishmaniasis (CL) is a health problem in 85 countries, which kills 72,800 to 119,600 people every year in Brazil. The available drugs display high toxicity and low efficacy what highlights the need for novel therapeutic alternatives to fight CL. Within this context, this project aims to exploit the enzyme dihydroorotate dehydrogenase (DHODH), as a target for the development of leishmanicidal drugs. DHODH catalyzes the conversion of dihydroorotate into orotate as part of the de novo pirimidine biosynthetic pathway and has been validated as a target against for proliferative and parasitic diseases.Accordingly, the aims of this project are: a) identify pockets in the protein surface that can accommodate ligands (hotspots); b) identify molecular fragments that bind to LmDHODH; c) develop molecular fragments into full grown lead compounds. In order to achieve these goals, the following techniques will be employed: Multiple Solvent Crystal Sreening (MSCS) and fragment screening by X-ray crystallography. The fragments shall have their affinity measured by biophysial/ biochemical assays ant their optimization shall be guided by in silico tools. We expect to develop lead-compounds that are useful for anti-leishmania drug development efforts and to contribute to the formation of human resources on structure-based and fragment-based drug development projects. (AU)

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