%0 Journal Article
%A Deng, Lisheng
%A Diao, Jiasheng
%A Chen, Pinhong
%A Pujari, Venugopal
%A Yao, Yuan
%A Cheng, Gang
%A Crick, Dean C.
%A V. Venkataram Prasad, B.
%A Song, Yongcheng
%D 2011
%T Inhibition of 1-Deoxy-d-Xylulose-5-Phosphate Reductoisomerase by Lipophilic Phosphonates: SAR, QSAR, and Crystallographic Studies
%U https://acs.figshare.com/articles/journal_contribution/Inhibition_of_1_Deoxy_d_Xylulose_5_Phosphate_Reductoisomerase_by_Lipophilic_Phosphonates_SAR_QSAR_and_Crystallographic_Studies/2630718
%R 10.1021/jm200363d.s001
%2 https://acs.figshare.com/ndownloader/files/4281814
%K MtDXR
%K QSAR
%K SAR
%K DXR inhibitors
%K 48 EcDXR inhibitors
%X 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 Ki 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.
%I ACS Publications