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

Abstract

BackgroundA 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.ResultsThe 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.ConclusionA 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.

Small-Molecule Inhibitors of IL-2/IL-2R: Lessons Learned and Applied

“…In the IL-2 case, unnatural peptidic linkers allowed rapid parallel synthesis and yielded novel inhibitors; however, more complex chemical strategies are sometimes required. Structure-based design and computational modeling of linkers can identify potential solutions (Mauser and Stahl 2007;Ertl and Schuffenhauer 2009); however, synthetic tractability is still a significant hurdle.…”

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“…Despite of this careful selection of functional groups, the database still contains a large fraction of problematic molecules in the perspective of synthetic and medicinal chemistry [31]. For example, 35% of GDB-13 molecules contain one or more non-aromatic N-N or N-O bond (in an oxime or hydrazone), 29% contain at least one ester, aldehyde, carbonate, sulfate, epoxide or aziridine, 63% contain at least one non-aromatic carbon-carbon double or triple bond, and 54% contain at least one 3-or 4-membered ring.…”

IADE: a system for intelligent automatic design of bioisosteric analogs

“…The modular architecture of the program, in which one can simply exchange modules from various software vendors, allows the use of best-in-class software for particular task without creating dependencies. The framework also has allowed us to use in-house tools, including substituent, linker and scaffold matchers [16], Hammett r descriptor [18], TPSA [19,37], synthetic accessibility score [21] and most importantly local QSAR models to tailor the optimization process. The IADE program is still in development, 1 but it already established itself as a useful help to modellers supporting medicinal chemistry projects, delivering several very useful novel ideas for the design of novel bioactive molecules.…”

“…Analogs are also checked to have physicochemical properties, particularly logP and TPSA, within user-desired ranges (these may be again defined in the IADE command file). A synthetic accessibility score developed in-house [21], a measure of the ease of synthesis based on several simple rules and fragment contributions, is used to filter out molecules that are too complex and would cause problems by synthesis. And, of course, analogs are checked for their uniqueness using their canonical SMILES representation; all duplicates are discarded.…”