Aix Marseille Univ, CNRS, Inserm, Institut Paoli Calmettes, CRCM , Marseille CEDEX 09 13273 , France.
Laboratoire de Chemoinformatique, CNRS UMR7140 , 1 rue Blaise Pascal , 67000 Strasbourg , France.
J Chem Inf Model. 2019 Apr 22;59(4):1472-1485. doi: 10.1021/acs.jcim.8b00960. Epub 2019 Apr 5.
We recently reported an integrated fragment-based optimization strategy called DOTS (Diversity Oriented Target-focused Synthesis) that combines automated virtual screening (VS) with semirobotized organic synthesis coupled to in vitro evaluation. The molecular modeling part consists of hit-to-lead chemistry, based on the growing paradigm. Here, we have extended the applicability of the DOTS strategy by adding new functionalities, allowing a generic chemistry-driven linking approach with a particular emphasis on covalent drugs. Indeed, the covalent mode of action can be described as a specific case of linking, where suitable linkers are sought to fuse a bound organic compound with a nucleophilic protein side chain. The proof of concept is established using three retrospective study cases in which known noncovalent inhibitors have been converted to covalent inhibitors. Our method is able to automatically design reference covalent inhibitors (and/or analogs) from an initial activated substructure and predict their binding mode. More importantly, the reference compounds are ranked high among several hundred putative adducts, demonstrating the utility of the approach to design covalent inhibitors.
我们最近报道了一种称为 DOTS（面向多样性的靶向合成）的集成片段优化策略，该策略将自动化虚拟筛选（VS）与半机器人有机合成相结合，并与体外评估相结合。基于不断发展的范例，分子建模部分包含了从命中到先导的化学，这里，我们通过添加新功能扩展了 DOTS 策略的适用性，允许采用通用的化学驱动连接方法，并特别强调共价药物。实际上，共价作用模式可以被描述为连接的一种特殊情况，其中需要寻找合适的连接子将结合的有机化合物与亲核蛋白质侧链融合。通过三个回顾性研究案例来证明概念，其中已知的非共价抑制剂已被转化为共价抑制剂。我们的方法能够自动设计初始激活子结构的参考共价抑制剂（和/或类似物），并预测它们的结合模式。更重要的是，参考化合物在数百种可能的加合物中排名很高，这证明了该方法设计共价抑制剂的实用性。
