Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut 06269, United States.
ACS Chem Biol. 2012 Feb 17;7(2):278-88. doi: 10.1021/cb200394t. Epub 2011 Nov 11.
Enzymes are often excellent drug targets. Yet drug pressure on an enzyme target often fosters the rise of cells with resistance-conferring mutations, some of which may compromise fitness and others that compensate to restore fitness. This review presents, first, a structural analysis of a diverse group of wild-type and mutant enzyme targets and, second, an in-depth analysis of five diverse targets to elucidate a broader perspective of the effects of resistance-conferring mutations on protein or organismal fitness. The structural analysis reveals that resistance-conferring mutations may introduce steric hindrance or eliminate critical interactions, as expected, but that they may also have indirect effects such as altering protein dynamics and enzyme kinetics. The structure-based development of the latest generation of inhibitors targeting HIV reverse transcriptase, P. falciparum and S. aureus dihydrofolate reductase, neuraminidase, and epithelial growth factor receptor (EGFR) tyrosine kinase, is highlighted to emphasize lessons that may be applied to future drug discovery to overcome mutation-induced resistance. Successful next-generation drugs tend to be more flexible and exploit a greater number of interactions mimicking those of the substrate with conserved residues.
酶通常是优秀的药物靶点。然而，药物对酶靶点的压力往往会促进具有耐药性的细胞的出现，其中一些可能会降低适应性，而另一些则会通过补偿来恢复适应性。这篇综述首先对一组不同的野生型和突变酶靶标进行了结构分析，其次对五个不同的靶标进行了深入分析，以阐明耐药性突变对蛋白质或生物体适应性的更广泛影响。结构分析表明，耐药性突变可能会引入空间位阻或消除关键相互作用，这是预期的，但也可能会产生间接影响，如改变蛋白质动力学和酶动力学。突出强调了基于结构的最新一代抑制剂的开发，这些抑制剂针对 HIV 逆转录酶、疟原虫和金黄色葡萄球菌二氢叶酸还原酶、神经氨酸酶和表皮生长因子受体（EGFR）酪氨酸激酶，以强调可能应用于未来药物发现以克服突变诱导的耐药性的经验教训。成功的下一代药物往往更具灵活性，并利用更多的相互作用来模拟与保守残基的底物相互作用。
