Fragment screening against Schistosoma mansoni dihydroorotate dehydrogenase: a modern approach for drug discovery

• Grant number: 19/04395-6
• Support Opportunities: Scholarships in Brazil - Master
• Start date: June 01, 2019
• End date: February 28, 2021
• Field of knowledge: Biological Sciences - Biophysics - Molecular Biophysics
• Principal Investigator: Maria Cristina Nonato
• Grantee: Renan Minin de Mori
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Fragment screening has emerged as an important tool in the pipeline of drug discovery. By using compounds of low molecular weight, it is possible to cover a broader range of the chemical space with fewer compounds. Fragments often bind with better ligand efficiencies than traditional screening and hits are capable of binding to a larger number of proteins than conventional 'drug-size' compounds. After the screening, results can be combined by growing, merging, or linking them to produce drug leads with higher affinity. This project focuses on the use of the fragment-based lead discovery technique to search for novel chemical entities as precursors of selective and potent inhibitors of Schistosoma mansoni dihydroorotate dehydrogenase (SmDHODH) with drug-like properties. Schistosoma mansoni is among the five species responsible for the schistosomiasis, a neglected parasitic disease caused by blood-dwelling trematodes of the genus Schistosoma. DHODH is a flavoenzyme that catalyzes the stereospecific oxidation of (S)-dihydroorotate (DHO) to orotate during the fourth and only redox step of the de novo pyrimidine nucleotide biosynthetic pathway. The depletion of nucleotide pools by the selective inhibition of DHODH has been exploited for the development of different therapeutic strategies, in particular to parasitic diseases. The present project represents a further step towards exploiting the inhibition of Schistosoma mansoni dihydroorotate dehydrogenase (SmDHODH) as a strategy to develop new therapeutics to fight schistosomiasis. (AU)

Scientific publications

(The scientific publications listed on this page originate from the Web of Science or SciELO databases. Their authors have cited FAPESP grant or fellowship project numbers awarded to Principal Investigators or Fellowship Recipients, whether or not they are among the authors. This information is collected automatically and retrieved directly from those bibliometric databases.)

DE MORI, RENAN M.; ALEIXO, MARIANA A. A.; ZAPATA, LUANA C. C.; CALIL, FELIPE A.; EMERY, FLAVIO S.; NONATO, M. CRISTINA. Structural basis for the function and inhibition of dihydroorotate dehydrogenase from Schistosoma mansoni. FEBS Journal, v. 288, n. 3, JUN 2020. (19/08376-6, 15/25099-5, 19/04395-6)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

MORI, Renan Minin de. Fragment screening against Schistosoma mansoni dihydroorotate dehydrogenase: a modern approach for drug discovery. 2021. Master's Dissertation - Universidade de São Paulo (USP). Faculdade de Ciências Farmacêuticas de Ribeirão Preto (PCARP/BC) Ribeirão Preto.