Estimation of synthetic accessibility score of drug-like molecules based on molecular complexity and fragment contributions

TLDR

Synthetic accessibility estimation is essential in drug discovery, and fragment contributions derived from one million PubChem molecules capture historical synthetic knowledge. The article develops and validates a synthetic accessibility scoring method (SAscore) ranging from 1 to 10, intended to rank large libraries for screening, hit selection, and de novo design. SAscore combines fragment contributions with a complexity penalty that accounts for non‑standard rings, stereochemistry, and size, and was validated against chemists’ assessments of 40 molecules. The SAscore correlates strongly with expert estimates (r² = 0.89), is computationally efficient, and can rank molecules for screening, hit selection, and de novo design.

Abstract

A method to estimate ease of synthesis (synthetic accessibility) of drug-like molecules is needed in many areas of the drug discovery process. The development and validation of such a method that is able to characterize molecule synthetic accessibility as a score between 1 (easy to make) and 10 (very difficult to make) is described in this article.The method for estimation of the synthetic accessibility score (SAscore) described here is based on a combination of fragment contributions and a complexity penalty. Fragment contributions have been calculated based on the analysis of one million representative molecules from PubChem and therefore one can say that they capture historical synthetic knowledge stored in this database. The molecular complexity score takes into account the presence of non-standard structural features, such as large rings, non-standard ring fusions, stereocomplexity and molecule size. The method has been validated by comparing calculated SAscores with ease of synthesis as estimated by experienced medicinal chemists for a set of 40 molecules. The agreement between calculated and manually estimated synthetic accessibility is very good with r2 = 0.89.A novel method to estimate synthetic accessibility of molecules has been developed. This method uses historical synthetic knowledge obtained by analyzing information from millions of already synthesized chemicals and considers also molecule complexity. The method is sufficiently fast and provides results consistent with estimation of ease of synthesis by experienced medicinal chemists. The calculated SAscore may be used to support various drug discovery processes where a large number of molecules needs to be ranked based on their synthetic accessibility, for example when purchasing samples for screening, selecting hits from high-throughput screening for follow-up, or ranking molecules generated by various de novo design approaches.