Estimation of synthetic accessibility score of drug-like molecules based on molecular complexity and fragment contributions
Open accessAbstract
BACKGROUND: 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. RESULTS: 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. CONCLUSION: 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.
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SA score is the most popular synthetic accessibility score.
“Among scores developed so far155 the most popular is SA score.156”
From QSAR without borders (2020) · cites this paper as [156]
SA score is calculated using contributions from fragment occurrences in PubChem compounds and a complexity penalty based on the number of chiral centers, rings, macrocyclic fragments, and the total number of atoms.
“It is calculated using contributions from fragment occurrences in PubChem compounds and a complexity penalty based on the number of chiral centers, rings, macrocyclic fragments, and the total number of atoms.”
From QSAR without borders (2020) · cites this paper as [156]
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“…SAscore values are computed with an exact approach that combines the fragment-based score representing the “ historical synthetic knowledge ” with the complexity-based score penalizing the presence of ring systems, such as spiro and fused rings, multiple stereo centers, and macrocycles [62].”
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“Abbreviations ADAM: Adaptative moment estimation; DRD2: Dopamine receptor D2; FEP: Free energy perturbation; FCD: Fréchet chemnet distance; GPCR: G protein-coupled receptor; QED: Quantitative estimate of drug-likeness; QSAR: Quantitative structure–activity relationship; SAscore: Synthetic accessibility score; SELFIES:…”
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- Authors
- Ertl, P., & Schuffenhauer, A.
- Affiliations
- Novartis (Switzerland) (CH)
- Corresponding author
- Ertl, Peter
- Venue
- Journal of Cheminformatics
- Published
- 2009-06-10
- Volume
- 1
- Issue
- 1
- Pages
- 8-8
- ISSN
- 1758-2946 (ISSN-L)
- PMC
- PMC3225829
- OpenAlex
- W2160592148
- Cited by
- 1,939
- References
- 16
- Citations by year
- 2026: 338 · 2025: 372 · 2024: 328 · 2023: 259 · 2022: 176 · 2021: 178 · 2020: 118 · 2019: 58 · 2018: 41 · 2017: 15 · 2016: 9 · 2015: 9 · 2014: 8 · 2013: 10 · 2012: 13
- FWCI
- 6.45
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Journal of Cheminformatics (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Topics
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and Characterization of Heterocyclic Compounds
- Keywords
- synthetic accessibility, molecular complexity, complexity penalty, drug-like molecules, PubChem, synthetic knowledge, ring size, de novo drug design
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