Generating Multibillion Chemical Space of Readily Accessible Screening Compounds

Oleksandr O Grygorenko; Dmytro S Radchenko; Igor Dziuba; Alexander Chuprina; Kateryna E Gubina; Yurii S Moroz

doi:10.1016/j.isci.2020.101681

Generating Multibillion Chemical Space of Readily Accessible Screening Compounds

iScience. 2020 Oct 15;23(11):101681. doi: 10.1016/j.isci.2020.101681. eCollection 2020 Nov 20.

Authors

Oleksandr O Grygorenko^{1

2}, Dmytro S Radchenko^{1

2}, Igor Dziuba³, Alexander Chuprina⁴, Kateryna E Gubina², Yurii S Moroz^{2

3}

Affiliations

¹ Enamine Ltd., Chervonotkatska Street 78, Kyiv 02094, Ukraine.
² Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, Kyiv 01601, Ukraine.
³ Chemspace, Chervonotkatska Street 78, Kyiv 02094, Ukraine.
⁴ UkrOrgSyntez Ltd. (UORSY), Yevhena Konovaltsia Street 29, Kyiv 01133, Ukraine.

Abstract

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.

Keywords: Chemical Compound; Cheminformatics; Computational Chemistry by Subject.

Grants and funding

R01 GM133836/GM/NIGMS NIH HHS/United States