title: Inhibition of 1-deoxy-D-xylulose-5-phosphate reductoisomerase by lipophilic phosphonates: SAR, QSAR, and crystallographic studies.
abstract: 1-Deoxy-D-xylulose-5-phosphate reductoisomerase (DXR) is a novel target for developing new antibacterial (including antituberculosis) and antimalaria drugs. Forty-one lipophilic phosphonates, representing a new class of DXR inhibitors, were synthesized, among which 5-phenylpyridin-2-ylmethylphosphonic acid possesses the most activity against E. coli DXR (EcDXR) with a K(i) of 420 nM. Structure-activity relationships (SAR) are discussed, which can be rationalized using our EcDXR:inhibitor structures, and a predictive quantitative SAR (QSAR) model is also developed. Since inhibition studies of DXR from Mycobacterium tuberculosis (MtDXR) have not been performed well, 48 EcDXR inhibitors with a broad chemical diversity were found, however, to generally exhibit considerably reduced activity against MtDXR. The crystal structure of a MtDXR:inhibitor complex reveals the flexible loop containing the residues 198-208 has no strong interactions with the 3,4-dichlorophenyl group of the inhibitor, representing a structural basis for the reduced activity. Overall, these results provide implications in the future design and development of potent DXR inhibitors.
authors.affiliation: Department of Pharmacology, Baylor College of Medicine, Houston, Texas 77030, United States.
authors.forename: Lisheng
authors.initials: L
authors.lastname: Deng
authors.forename: Jiasheng
authors.initials: J
authors.lastname: Diao
authors.forename: Pinhong
authors.initials: P
authors.lastname: Chen
authors.forename: Venugopal
authors.initials: V
authors.lastname: Pujari
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yao
authors.forename: Gang
authors.initials: G
authors.lastname: Cheng
authors.forename: Dean C
authors.initials: DC
authors.lastname: Crick
authors.forename: B V Venkataram
authors.initials: BV
authors.lastname: Prasad
authors.forename: Yongcheng
authors.initials: Y
authors.lastname: Song
mesh_terms: D019747:Aldose-Ketose Isomerases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry; D018360:Crystallography, X-Ray; D004926:Escherichia coli / Q000201:enzymology; D008958:Models, Molecular; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000737:chemistry; D009169:Mycobacterium tuberculosis / Q000201:enzymology; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000737:chemistry; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D000995:Antitubercular Agents; D009097:Multienzyme Complexes; D063065:Organophosphonates; D010088:Oxidoreductases; C114231:1-deoxy-D-xylulose 5-phosphate reductoisomerase; D019747:Aldose-Ketose Isomerases