INHA WITH INHIBITORS

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 InhA是参与结核分枝杆菌II型脂肪酸生物合成（FAS II）的烯酰-酰基载体蛋白还原酶。目前的结核病药物INH已被证明靶向InhA，许多来自其他生物体的FAS II烯酰还原酶也是经验证的药物靶标。我们小组开发的新型InhA抑制剂利用了与INH不同的抑制机制，可以绕过INH耐药性，并且它们是缓慢结合抑制剂，由于停留时间长，预计将显示出更好的体内功效。我们正在使用晶体学来研究缓慢抑制的结构基础。将研究InhA底物结合环的有序性和构象与结合动力学的相关性，这些信息将用于设计具有更好结合动力学的抑制剂。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. InhA is the enoyl-acyl carrier protein reductase involved in type II fatty acid biosynthesis (FAS II) of Mycobacterium tuberculosis. The current TB drug INH has been shown to target InhA, and many FAS II enoylreductases from other organisms are also validated drug targets. The novel InhA inhibitors developed in our group utilize a different mechanism of inhibition from INH and can bypass INH resistance, and they are slow binding inhibitors that are expected to show better in vivo efficacy because of long residence time. We are using crystallography to study the structural basis of slow inhibition. Correlation of ordering and conformation of the InhA substrate binding loop with binding kinetics will be investigated and such information will be used for designing inhibitors with better binding kinetics.