Sun Hui-Yong, Hou Ting-Jun, Zhang Hong-Yu
National Key Laboratory of Crop Genetic Improvement, Agricultural Bioinformatics Key Laboratory of Hubei Province, College of Informatics, Huazhong Agricultural University, Wuhan 430070, PR China; Institute of Functional Nano & Soft Materials (FUNSOM) and Collaborative Innovation Center of Suzhou Nano Science and Technology, Soochow University, Suzhou, Jiangsu 215123, PR China.
Institute of Functional Nano & Soft Materials (FUNSOM) and Collaborative Innovation Center of Suzhou Nano Science and Technology, Soochow University, Suzhou, Jiangsu 215123, PR China; College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, PR China.
Drug Discov Today. 2014 Dec;19(12):1836-40. doi: 10.1016/j.drudis.2014.09.013. Epub 2014 Sep 26.
Chemical drugs provide alternative treatments for genetic diseases in addition to gene therapy. Inherited diseases arising from gain-of-function (GOF) or loss-of-function (LOF) mutations of certain genes can be ameliorated by the antagonists and/or agonists of the target genes. However, a premise for this chemical therapeutic strategy is that the GOF/LOF mutations in drug targets have a negligible influence on drug-target binding. Here, we analyze the disease-causing mutations [derived from Online Mendelian Inheritance in Man (OMIM)] in successful drug targets. We found that >70% of the mutations are located far from the drug-binding sites (>12 Å), and most of the other mutations are unlikely to have adverse effects on drug binding, supporting the chemical strategy for combating genetic diseases.
除了基因疗法外，化学药物为遗传疾病提供了替代治疗方法。由某些基因的功能获得（GOF）或功能丧失（LOF）突变引起的遗传性疾病可以通过靶基因的拮抗剂和/或激动剂得到改善。然而，这种化学治疗策略的一个前提是药物靶点中的GOF/LOF突变对药物-靶点结合的影响可以忽略不计。在这里，我们分析了成功的药物靶点中的致病突变[源自《人类孟德尔遗传在线》（OMIM）]。我们发现超过70%的突变位于远离药物结合位点的位置（>12 Å），并且大多数其他突变不太可能对药物结合产生不利影响，这支持了对抗遗传疾病的化学策略。
