Generating Multibillion Chemical Space of Readily Accessible Screening Compounds

• Published in: iScience Vol. 23; no. 11; p. 101681
• Main Authors: Grygorenko, Oleksandr O., Radchenko, Dmytro S., Dziuba, Igor, Chuprina, Alexander, Gubina, Kateryna E., Moroz, Yurii S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.11.2020; Elsevier
• Subjects: Chemical Compound; Cheminformatics; Computational Chemistry by Subject; Computational Chemistry by Subject; Cheminformatics; Chemical Compound
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2020.101681

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. [Display omitted] •A strategy for ultra-large readily accessible (REAL) compound libraries is described•Pre-validated two- or three-step three-component reaction sequences are used•A 29-billion chemical space with ∼80% synthesis success rate has been easily obtained Chemical Compound; Cheminformatics; Computational Chemistry by Subject