title: Virtual Screening and X-ray Crystallography Identify Non-Substrate Analog Inhibitors of Flavin-Dependent Thymidylate Synthase.
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.
authors: Department of Life Sciences, University of Modena and Reggio Emilia , Via Campi, 103, 41125 Modena, Italy.
authors: Rosaria
authors: R
authors: Luciani
authors: Department of Life Sciences, University of Modena and Reggio Emilia , Via Campi, 103, 41125 Modena, Italy.
authors: Puneet
authors: P
authors: Saxena
authors: Department of Biochemistry, University of Cambridge , 80 Tennis Court Road, Cambridge, CB2 1GA, United Kingdom.
authors: Sachin
authors: S
authors: Surade
authors: Department of Life Sciences, University of Modena and Reggio Emilia , Via Campi, 103, 41125 Modena, Italy.
authors: Matteo
authors: M
authors: Santucci
authors: Department of Life Sciences, University of Modena and Reggio Emilia , Via Campi, 103, 41125 Modena, Italy.|Tydock Pharma srl , Strada Gherbella 294/B, 41126 Modena, Italy.
authors: Alberto
authors: A
authors: Venturelli
authors: Department of Life Sciences, University of Modena and Reggio Emilia , Via Campi, 103, 41125 Modena, Italy.
authors: Chiara
authors: C
authors: Borsari
authors: Department of Biomedical Sciences, Metabolic and Neural Sciences, University of Modena and Reggio Emilia , Via Campi, 287, 41125 Modena, Italy.
authors: Gaetano
authors: G
authors: Marverti
authors: Department of Life Sciences, University of Modena and Reggio Emilia , Via Campi, 103, 41125 Modena, Italy.
authors: Glauco
authors: G
authors: Ponterini
authors: Department of Life Sciences, University of Modena and Reggio Emilia , Via Campi, 103, 41125 Modena, Italy.
authors: Stefania
authors: S
authors: Ferrari
authors: Department of Biochemistry, University of Cambridge , 80 Tennis Court Road, Cambridge, CB2 1GA, United Kingdom.
authors: Tom L
authors: TL
authors: Blundell
authors: Department of Life Sciences, University of Modena and Reggio Emilia , Via Campi, 103, 41125 Modena, Italy.
authors: Maria Paola
authors: MP
authors: Costi
mesh_terms: D000995:Antitubercular Agents / Q000737:chemistry* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D005415:Flavins / Q000378:metabolism; D006801:Humans; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D011724:Pyridazines / Q000737:chemistry* / Q000494:pharmacology*; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D014376:Tuberculosis / Q000188:drug therapy
chemical_list: D000995:Antitubercular Agents; D004791:Enzyme Inhibitors; D005415:Flavins; D011724:Pyridazines; D013940:Thymidylate Synthase