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Virtual Screening and X-ray Crystallography Identify Non-Substrate Analog Inhibitors of Flavin-Dependent Thymidylate Synthase
- Source :
- Journal of medicinal chemistry. 59(19)
- Publication Year :
- 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 (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.
- Subjects :
- 0301 basic medicine
medicine.drug_class
Stereochemistry
Antitubercular Agents
Flavin group
Substrate analog
Antimycobacterial
Crystallography, X-Ray
01 natural sciences
Thymidylate synthase
Mycobacterium tuberculosis
03 medical and health sciences
chemistry.chemical_compound
Flavins
Drug Discovery
medicine
Humans
Tuberculosis
Enzyme Inhibitors
Virtual screening
biology
010405 organic chemistry
Drug discovery
Chemistry
Active site
Thymidylate Synthase
biology.organism_classification
3. Good health
0104 chemical sciences
Pyridazines
030104 developmental biology
Drug Design
biology.protein
Molecular Medicine
Subjects
Details
- ISSN :
- 15204804
- Volume :
- 59
- Issue :
- 19
- Database :
- OpenAIRE
- Journal :
- Journal of medicinal chemistry
- Accession number :
- edsair.doi.dedup.....e60d3d60f77ab94f8d4fc79ad0f9bd0b