Exploring compound screening strategies to identify inhibitors of N5, N10: methylenetetrahydrofolate dehydrogenase-cyclohydrolase from Xanthomonas albilineans

• Grant number: 16/16038-5
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: November 21, 2016
• End date: November 20, 2017
• Field of knowledge: Biological Sciences - Biophysics - Molecular Biophysics
• Principal Investigator: Rafael Victorio Carvalho Guido
• Grantee: Renata Vieira Bueno
• Supervisor: William Nigel Hunter
• Host Institution: Instituto de Física de São Carlos (IFSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil
• Institution abroad: University of Dundee, Scotland
• Associated to the scholarship: 13/04737-8 - Discovery and Design of Folate Synthesis Inhibitors as Agrochemicals Candidates for Sugar Cane Culture, BP.DR

Abstract

Sugarcane derivatives stand out as major contributors to renewable energy sources in bioenergy production. However, the occurrence of severe diseases affects the productivity of sugarcane crops. One such condition is leaf scald disease, which is caused by the gram-negative bacteria Xanthomonas albilineans. Leaf scald disease has a dramatic impact on crop productivity, including reduced yields and reducing the quality of the juice. The absence of chemical or biological agents to treat the disease justifies research and the development of new bioactive molecules as effective and selective agrochemicals. An attractive metabolic pathway explored for this purpose is the biosynthesis of folates. Enzymes involved in synthesis and modification of folates are validated molecular targets for inhibitor design. In this context, the enzyme N5, N10 - methylenetetrahydrofolate dehydrogenase-cyclohydrolase (XaFolD) is essential for biosynthesis of folates and it has been selected for structural and functional characterization. Previous kinetic and structural characterization of XaFolD carried out in our lab provides the basis for exploring the enzyme as a target for inhibitor screening and discovery. In this proposal, we will investigate the association of High Throughput Screening assays (HTS) and Virtual Screening (VS) methods to explore diverse chemical scaffolds directed towards the discovery of XaFolD inhibitors. The ligands identified by these strategies will be characterized by biophysical and kinetic methods to better understand the molecular interactions and mode of inhibition. The most potent XaFolD inhibitors will be assessed in vitro against X. albilineans. The successful outcomes of our integrated and multidisciplinary strategy may identify XaFolD inhibitors as important lead candidates for development and subsequent agrochemical use. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

BUENO, RENATA; DAWSON, ALICE; HUNTER, WILLIAM N.. An assessment of three human methylenetetrahydrofolate dehydrogenase/cyclohydrolase-ligand complexes following further refinement. ACTA CRYSTALLOGRAPHICA SECTION F-STRUCTURAL BIOLOGY COMMUNICATIONS, v. 75, n. 3, p. 148-152, MAR 2019. (16/16038-5)

BUENO, RENATA, V; DAVIS, SAMUEL; DAWSON, ALICE; ONDACHI, PAULINE W.; CARROLL, F. IVY; HUNTER, WILLIAM N.. Interactions between 2 '-fluoro-(carbamoyl-pyridinyl)deschloroepibatidine analogues and acetylcholine-binding protein inform on potent antagonist activity against nicotinic receptors. ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, v. 78, p. 10-pg., 2022-03-01. (16/16038-5)

BUENO, RENATA; DAWSON, ALICE; HUNTER, WILLIAM N.. An assessment of three human methylenetetrahydrofolate dehydrogenase/cyclohydrolase-ligand complexes following further refinement. ACTA CRYSTALLOGRAPHICA SECTION F-STRUCTURAL BIOLOGY COMMUNICATIONS, v. 75, p. 5-pg., 2019-03-01. (16/16038-5)