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 ThyX in complex with a non-substrate analog inhibitor. Given the active site similarities between 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.

Virtual Screening and X-ray Crystallography Identify Non-Substrate Analog Inhibitors of Flavin-Dependent Thymidylate Synthase / Luciani, Rosaria; Saxena, Puneet; Surade, Sachin; Santucci, Matteo; Venturelli, Alberto; Borsari, Chiara; Marverti, Gaetano; Ponterini, Glauco; Ferrari, Stefania; Blundell, Tom L; Costi, Maria Paola. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - ELETTRONICO. - 59:19(2016), pp. 9269-9275. [10.1021/acs.jmedchem.6b00977]

Virtual Screening and X-ray Crystallography Identify Non-Substrate Analog Inhibitors of Flavin-Dependent Thymidylate Synthase

LUCIANI, Rosaria;SAXENA, PUNEET;SANTUCCI, MATTEO;Venturelli, Alberto;BORSARI, CHIARA;MARVERTI, Gaetano;PONTERINI, Glauco;FERRARI, Stefania;COSTI, Maria Paola
2016

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 ThyX in complex with a non-substrate analog inhibitor. Given the active site similarities between 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.
2016
29-set-2016
59
19
9269
9275
Virtual Screening and X-ray Crystallography Identify Non-Substrate Analog Inhibitors of Flavin-Dependent Thymidylate Synthase / Luciani, Rosaria; Saxena, Puneet; Surade, Sachin; Santucci, Matteo; Venturelli, Alberto; Borsari, Chiara; Marverti, Gaetano; Ponterini, Glauco; Ferrari, Stefania; Blundell, Tom L; Costi, Maria Paola. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - ELETTRONICO. - 59:19(2016), pp. 9269-9275. [10.1021/acs.jmedchem.6b00977]
Luciani, Rosaria; Saxena, Puneet; Surade, Sachin; Santucci, Matteo; Venturelli, Alberto; Borsari, Chiara; Marverti, Gaetano; Ponterini, Glauco; Ferrar...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1115867
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