Institute of Applied Synthetic Chemistry , TU Wien , Getreidemarkt 9/163 , 1060 Vienna , Austria.
Department of Pharmaceutical Chemistry , University of Vienna , Althanstrasse 14 , 1090 Vienna , Austria.
J Chem Inf Model. 2018 Aug 27;58(8):1682-1696. doi: 10.1021/acs.jcim.8b00199. Epub 2018 Aug 8.
The structural resolution of a bound ligand-receptor complex is a key asset to efficiently drive lead optimization in drug design. However, structural resolution of many drug targets still remains a challenging endeavor. In the absence of structural knowledge, scientists resort to structure-activity relationships (SARs) to promote compound development. In this study, we incorporated ligand-based knowledge to formulate a docking scoring function that evaluates binding poses for their agreement with a known SAR. We showcased this protocol by identifying the binding mode of the pyrazoloquinolinone (PQ) CGS-8216 at the benzodiazepine binding site of the GABA receptor. Further evaluation of the final pose by molecular dynamics and free energy simulations revealed a close proximity between the pendent phenyl ring of the PQ and γ2D56, congruent with the low potency of carboxyphenyl analogues. Ultimately, we introduced the γ2D56A mutation and in fact observed a 10-fold potency increase in the carboxyphenyl analogue, providing experimental evidence in favor of our binding hypothesis.
配体-受体复合物的结构解析是药物设计中有效推动先导化合物优化的关键因素。然而，许多药物靶点的结构解析仍然是一项具有挑战性的工作。在缺乏结构知识的情况下，科学家们诉诸于构效关系（SARs）来促进化合物的开发。在本研究中，我们结合配体知识，制定了一种对接评分函数，用于评估结合构象与已知 SAR 的一致性。我们通过确定吡唑并喹啉酮（PQ）CGS-8216 在 GABA 受体苯二氮䓬结合位点的结合模式来展示该方案。通过分子动力学和自由能模拟对最终构象的进一步评估表明，PQ 的悬苯基与 γ2D56 非常接近，这与羧苯基类似物的低效力一致。最终，我们引入了 γ2D56A 突变，实际上观察到羧苯基类似物的效力增加了 10 倍，为我们的结合假说提供了实验证据。
