Computational Design and Discovery of Conformationally Flezible Inhibitors of Acetohydrozyacid Synthase to Overcome Drug Resistance Associated with the W586L Mutation
Acetohydroxyacid synthase (AHAS, also known as acetolactate synthase, EC 2.2.1.6 (formerly EC 4.1.3.18)) has attracted atten tion for many years as a potential target for inhibitors to be used as herbicides and antibiotics. Despite the great success of commercial AHAS inhibitors over the past decades, drug re sistance has become one of the most serious problems to overcome.2 In most cases, resistance to AHAS-inhibiting prod ucts has been shown to be caused by an alteration in the AHAS enzyme itself. Single point mutations that confer resist ance to AHAS inhibitors include A117T, P192A, P192S, P192E, P192L, A200V, and W586L Saccharomyces cerevisiae AHAS resi due numbering).2a Among these, W586L is the most compre hensively characterized mutation, which results in at least 10-fold resistance to all types of AHAS inhibitors.2d Therefore, the design of novel compounds that block the activity of the W586L mutant form has become one of the biggest challenges in this field. Herein we report the first computational design that has led to the discovery of 2-aroxyl-1,2,4-triazolo1,5-cpyr-imidines that have the same level of inhibitory activity against both wild-type AHAS and its W586L mutant. The present study demonstrates that the computational design approach based on the analysis of ligand conformational flexibility in the bind ing pocket holds promise for the rational design of conforma tionally flexible inhibitors of enzymes to overcome drug resist ance.A general understanding of the molecular mechanisms behind some representative commercially available AHAS in hibitors provides useful clues for further molecular design against drug resistance. Three structurally diverse AHAS inhibitors, chlorsulfuron (CS), bispyribac (BP), and flumetsulam (FS) (Figure 1) were considered for this purpose.
Feng-Qin Ji Cong-Wei Niu Chao-Nan Chen Qiong Chen Guang-Fu Yang Zhen Xi Chang-Guo Zhan
Key Laboratory of Pesticide & Chemical Biology Ministry of Education, College of Chemistry Central C Key Laboratory of Pesticide & Chemical Biology Ministry of Education, College of Chemistry Central C State Key Laboratory of Elemento-Organic Chemistry Nankai University, Tianjin 300071 (P.R.China) Department of Pharmaceutical Sciences University of Kentucky, College of Pharmacy 725 Rose Street, L
国际会议
广州
英文
183-186
2008-11-01（万方平台首次上网日期，不代表论文的发表时间）