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Virtual screening and X-ray crystallography identify non-substrate analog inhibitors of flavin-dependent thymidylate synthase

DOI: 10.1021/acs.jmedchem.6b00977 DOI Help

Authors: Rosaria Luciani (University of Modena and Reggio Emilia) , Puneet Saxena (University of Modena and Reggio Emilia) , Sachin Surade (University of Cambridge) , Matteo Santucci (University of Modena and Reggio Emilia) , Alberto Venturelli (Tydock Pharma srl) , Chiara Borsari (University of Modena and Reggio Emilia) , Gaetano Marverti (University of Modena and Reggio Emilia) , Glauco Ponterini (University of Modena and Reggio Emilia) , Stefania Ferrari (University of Modena and Reggio Emilia) , Tom L. Blundell (University of Cambridge) , Maria Paola Costi (University of Modena and Reggio Emilia)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry , VOL 59 , PAGES 9269 - 9275

State: Published (Approved)
Published: October 2016
Diamond Proposal Number(s): 9537 , 9007

Abstract: Thymidylate synthase X (ThyX) represents an attractive target for tuberculosis drug discovery. Herein, we selected 16 compounds through a virtual screening approach. We solved the first X-ray crystal structure of Thermatoga maritima (Tm) ThyX in complex with a nonsubstrate analog inhibitor. Given the active site similarities between Mycobacterium tuberculosis ThyX (Mtb-ThyX) and Tm-ThyX, our crystal structure paves the way for a structure-based design of novel antimycobacterial compounds. The 1H-imidazo[4,5-d]pyridazine was identified as scaffold for the development of Mtb-ThyX inhibitors.

Journal Keywords: Crystallography; X-rays; Crystal structure; Inhibitors; Inhibition

Diamond Keywords: Tuberculosis (TB); Bacteria

Subject Areas: Medicine, Chemistry, Biology and Bio-materials

Instruments: I03-Macromolecular Crystallography

Added On: 22/11/2016 15:30

Discipline Tags:

Pathogens Infectious Diseases Health & Wellbeing Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)