Grygorenko Oleksandr O, Radchenko Dmytro S, Dziuba Igor, Chuprina Alexander, Gubina Kateryna E, Moroz Yurii S
Enamine Ltd., Chervonotkatska Street 78, Kyiv 02094, Ukraine.
Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, Kyiv 01601, Ukraine.
iScience. 2020 Oct 15;23(11):101681. doi: 10.1016/j.isci.2020.101681. eCollection 2020 Nov 20.
An approach to the generation of ultra-large chemical libraries of readily accessible ("REAL") compounds is described. The strategy is based on the use of two- or three-step three-component reaction sequences and available starting materials with pre-validated chemical reactivity. After the preliminary parallel experiments, the methods with at least ∼80% synthesis success rate (such as acylation - deprotection - acylation of monoprotected diamines or amide formation - click reaction with functionalized azides) can be selected and used to generate the target chemical space. It is shown that by using only on the two aforementioned reaction sequences, a nearly 29-billion compound library is easily obtained. According to the predicted physico-chemical descriptor values, the generated chemical space contains large fractions of both drug-like and "beyond rule-of-five" members, whereas the strictest lead-likeness criteria (the so-called Churcher's rules) are met by the lesser part, which still exceeds 22 million.
本文描述了一种生成易于获取的（“REAL”）化合物的超大化学库的方法。该策略基于使用两步或三步三组分反应序列以及具有预先验证的化学反应性的可用起始材料。经过初步的平行实验后，可以选择合成成功率至少约为80%的方法（例如单保护二胺的酰化-脱保护-酰化或酰胺形成-与功能化叠氮化物的点击反应）并用于生成目标化学空间。结果表明，仅使用上述两个反应序列，就很容易获得近290亿个化合物库。根据预测的物理化学描述符值，生成的化学空间包含很大比例的类药物和“超越五规则”成员，而符合最严格的类先导物标准（所谓的Churcher规则）的部分较少，但仍超过2200万。
