{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,4,25]],"date-time":"2025-04-25T04:19:19Z","timestamp":1745554759946,"version":"3.40.4"},"reference-count":29,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,4,24]],"date-time":"2025-04-24T00:00:00Z","timestamp":1745452800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,4,24]],"date-time":"2025-04-24T00:00:00Z","timestamp":1745452800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100000266","name":"EPSRC","doi-asserted-by":"crossref","award":["EP\/N509735\/1"],"award-info":[{"award-number":["EP\/N509735\/1"]}],"id":[{"id":"10.13039\/501100000266","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Cheminform"],"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>The typical way in which lead optimisation (LO) series are represented in the medicinal chemistry literature is as Markush structures and associated R-group tables. The Markush structure shows a central core or molecular scaffold that is common to the series with R groups that indicate the points of variability that have been explored in the series. The associated R-group table shows the substituent combinations that exist in individual molecules in the series together with properties of those compounds. This format provides an intuitive way of visualising any structure\u2013activity relationship (SAR) that is present. Automated approaches that attempt to reproduce this well understood format, such as the SAR map, are based on maximum common substructure approaches and do not take account of small changes that may be made to the core structure itself or of the situation where more than one core exists in the data. Here we describe an automated approach to represent LO series that is based on reduced graph descriptions of molecules. A publicly available LO dataset from a drug discovery programme at GSK is analysed to show how the method can group together compounds from the same series even when there are small substructural differences within the core of the series while also being able to identify different related compound series. The resulting visualisation is useful in identifying areas where series are under explored and for mapping design ideas onto the current dataset. The code to generate the visualisations is released into the public domain to promote further research in this area.<\/jats:p>\n          <jats:p>\n            <jats:bold>Scientific contribution<\/jats:bold>: We describe a software tool for analysing lead optimisation series using reduced graph representations of molecules. The representation allows compounds that have similar but not identical chemical scaffolds to be grouped together and is, therefore, an advance on methods that are based on the more traditional Markush structure and SAR tables. The software is a useful addition to the med chem toolbox as it can provide a holistic view of lead optimisation data by representing what might otherwise be seen as separate series as a single series of compounds.<\/jats:p>","DOI":"10.1186\/s13321-025-01002-7","type":"journal-article","created":{"date-parts":[[2025,4,24]],"date-time":"2025-04-24T11:55:29Z","timestamp":1745495729000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Visualising lead optimisation series using reduced graphs"],"prefix":"10.1186","volume":"17","author":[{"given":"Jessica","family":"Stacey","sequence":"first","affiliation":[]},{"given":"Baptiste","family":"Canault","sequence":"additional","affiliation":[]},{"given":"Stephen D.","family":"Pickett","sequence":"additional","affiliation":[]},{"given":"Valerie J.","family":"Gillet","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2025,4,24]]},"reference":[{"key":"1002_CR1","doi-asserted-by":"publisher","first-page":"4062","DOI":"10.1021\/acs.jmedchem.5b01746","volume":"59","author":"MY Hu","year":"2016","unstructured":"Hu MY, Stumpfe D, Bajorath J (2016) Computational exploration of molecular scaffolds in medicinal chemistry. J Med Chem 59:4062\u20134076. https:\/\/doi.org\/10.1021\/acs.jmedchem.5b01746","journal-title":"J Med Chem"},{"key":"1002_CR2","doi-asserted-by":"publisher","first-page":"5926","DOI":"10.1021\/jm070845m","volume":"50","author":"DK Agrafiotis","year":"2007","unstructured":"Agrafiotis DK, Shemanarev M, Connolly PJ et al (2007) SAR maps: a new SAR visualization technique for medicinal chemists. J Med Chem 50:5926\u20135937. https:\/\/doi.org\/10.1021\/jm070845m","journal-title":"J Med Chem"},{"key":"1002_CR3","doi-asserted-by":"publisher","first-page":"1215","DOI":"10.1021\/jm201362h","volume":"55","author":"AM Wassermann","year":"2012","unstructured":"Wassermann AM, Bajorath J (2012) Directed R-group combination graph: a methodology to uncover structure-activity relationship patterns in a series of analogues. J Med Chem 55:1215\u20131226. https:\/\/doi.org\/10.1021\/jm201362h","journal-title":"J Med Chem"},{"key":"1002_CR4","doi-asserted-by":"publisher","first-page":"7667","DOI":"10.1021\/acs.jmedchem.6b00906","volume":"59","author":"D Stumpfe","year":"2016","unstructured":"Stumpfe D, Dimova D, Bajorath J (2016) Computational method for the systematic identification of analog series and key compounds representing series and their biological activity profiles. J Med Chem 59:7667\u20137676. https:\/\/doi.org\/10.1021\/acs.jmedchem.6b00906","journal-title":"J Med Chem"},{"key":"1002_CR5","doi-asserted-by":"publisher","first-page":"2887","DOI":"10.1021\/jm9602928","volume":"39","author":"GW Bemis","year":"1996","unstructured":"Bemis GW, Murcko MA (1996) The properties of known drugs. 1. Molecular frameworks. J Med Chem 39:2887\u20132893. https:\/\/doi.org\/10.1021\/jm9602928","journal-title":"J Med Chem"},{"key":"1002_CR6","doi-asserted-by":"publisher","first-page":"3331","DOI":"10.1021\/acs.jcim.0c00296","volume":"60","author":"F Kruger","year":"2020","unstructured":"Kruger F, Stiefl N, Landrum GA (2020) rdScaffoldNetwork: the Scaffold network implementation in RDKit. J Chem Inf Model 60:3331\u20133335. https:\/\/doi.org\/10.1021\/acs.jcim.0c00296","journal-title":"J Chem Inf Model"},{"key":"1002_CR7","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1021\/ci600338x","volume":"47","author":"A Schuffenhauer","year":"2007","unstructured":"Schuffenhauer A, Ertl P, Roggo S et al (2007) The Scaffold tree \u2212 visualization of the scaffold universe by hierarchical scaffold classification. J Chem Inf Model 47:47\u201358. https:\/\/doi.org\/10.1021\/ci600338x","journal-title":"J Chem Inf Model"},{"key":"1002_CR8","doi-asserted-by":"publisher","first-page":"581","DOI":"10.1038\/nchembio.187","volume":"5","author":"S Wetzel","year":"2009","unstructured":"Wetzel S, Klein K, Renner S et al (2009) Interactive exploration of chemical space with Scaffold Hunter. Nat Chem Biol 5:581\u2013583. https:\/\/doi.org\/10.1038\/nchembio.187","journal-title":"Nat Chem Biol"},{"key":"1002_CR9","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1021\/ci900416a","volume":"50","author":"E Lounkine","year":"2010","unstructured":"Lounkine E, Wawer M, Wassermann AM, Bajorath J (2010) SARANEA: a freely available program to mine structure\u2212activity and structure\u2212selectivity relationship information in compound data sets. J Chem Inf Model 50:68\u201378. https:\/\/doi.org\/10.1021\/ci900416a","journal-title":"J Chem Inf Model"},{"key":"1002_CR10","doi-asserted-by":"publisher","first-page":"3584","DOI":"10.1093\/bioinformatics\/btw523","volume":"32","author":"J Lu","year":"2016","unstructured":"Lu J, Carlson HA (2016) ChemTreeMap: an interactive map of biochemical similarity in molecular datasets. Bioinformatics 32:3584\u20133592. https:\/\/doi.org\/10.1093\/bioinformatics\/btw523","journal-title":"Bioinformatics"},{"key":"1002_CR11","doi-asserted-by":"publisher","first-page":"6075","DOI":"10.1021\/jm800867g","volume":"51","author":"M Wawer","year":"2008","unstructured":"Wawer M, Peltason L, Weskamp N et al (2008) Structure\u2212activity relationship anatomy by network-like similarity graphs and local structure\u2212activity relationship indices. J Med Chem 51:6075\u20136084. https:\/\/doi.org\/10.1021\/jm800867g","journal-title":"J Med Chem"},{"key":"1002_CR12","doi-asserted-by":"publisher","first-page":"e202400265","DOI":"10.1002\/minf.202400265","volume":"44","author":"AA Orlov","year":"2025","unstructured":"Orlov AA, Akhmetshin TN, Horvath D et al (2025) From high dimensions to human insight: exploring dimensionality reduction for chemical space visualization. Mol Inform 44:e202400265. https:\/\/doi.org\/10.1002\/minf.202400265","journal-title":"Mol Inform"},{"key":"1002_CR13","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1021\/ci050465e","volume":"46","author":"K Birchall","year":"2006","unstructured":"Birchall K, Gillet VJ, Harper G, Pickett SD (2006) Training similarity measures for specific activities: application to reduced graphs. J Chem Inf Model 46:577\u2013586. https:\/\/doi.org\/10.1021\/ci050465e","journal-title":"J Chem Inf Model"},{"key":"1002_CR14","doi-asserted-by":"publisher","first-page":"260","DOI":"10.1021\/ci00002a011","volume":"31","author":"VJ Gillet","year":"1991","unstructured":"Gillet VJ, Downs GM, Holliday JD et al (1991) Computer storage and retrieval of generic chemical structures in patents. 13. Reduced graph generation. J Chem Inf Comput Sci 31:260\u2013270. https:\/\/doi.org\/10.1021\/ci00002a011","journal-title":"J Chem Inf Comput Sci"},{"key":"1002_CR15","doi-asserted-by":"publisher","first-page":"338","DOI":"10.1021\/ci025592e","volume":"43","author":"VJ Gillet","year":"2003","unstructured":"Gillet VJ, Willett P, Bradshaw J (2003) Similarity searching using reduced graphs. J Chem Inf Comput Sci 43:338\u2013345. https:\/\/doi.org\/10.1021\/ci025592e","journal-title":"J Chem Inf Comput Sci"},{"key":"1002_CR16","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1021\/ci050347r","volume":"46","author":"EJ Barker","year":"2006","unstructured":"Barker EJ, Buttar D, Cosgrove DA et al (2006) Scaffold hopping using clique detection applied to reduced graphs. J Chem Inf Model 46:503\u2013511. https:\/\/doi.org\/10.1021\/ci050347r","journal-title":"J Chem Inf Model"},{"key":"1002_CR17","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1021\/ci00055a007","volume":"27","author":"VJ Gillet","year":"1987","unstructured":"Gillet VJ, Downs GM, Ling A et al (1987) Computer storage and retrieval of generic chemical structures in patents. 8. Reduced chemical graphs and their applications in generic chemical structure retrieval. J Chem Inf Comput Sci 27:126\u2013137. https:\/\/doi.org\/10.1021\/ci00055a007","journal-title":"J Chem Inf Comput Sci"},{"key":"1002_CR18","doi-asserted-by":"publisher","first-page":"1578","DOI":"10.1021\/ci4007547","volume":"54","author":"S Wollenhaupt","year":"2014","unstructured":"Wollenhaupt S, Baumann K (2014) inSARa: intuitive and interactive SAR interpretation by reduced graphs and hierarchical MCS-based network navigation. J Chem Inf Model 54:1578\u20131595. https:\/\/doi.org\/10.1021\/ci4007547","journal-title":"J Chem Inf Model"},{"key":"1002_CR19","unstructured":"James CA, Weininger D, Delany J. Daylight Theory Manual. 2020. https:\/\/www.daylight.com\/dayhtml\/doc\/theory\/theory.smarts.html. Accessed 23 Sep 2020."},{"key":"1002_CR20","doi-asserted-by":"publisher","first-page":"354","DOI":"10.1021\/ci600444g","volume":"47","author":"EJ Gardiner","year":"2007","unstructured":"Gardiner EJ, Gillet VJ, Willett P, Cosgrove DA (2007) Representing clusters using a maximum common edge substructure algorithm applied to reduced graphs and molecular graphs. J Chem Inf Model 47:354\u2013366. https:\/\/doi.org\/10.1021\/ci600444g","journal-title":"J Chem Inf Model"},{"key":"1002_CR21","first-page":"1","volume-title":"Chemoinformatics: concepts, methods, and tools for drug discovery","author":"GM Maggiora","year":"2004","unstructured":"Maggiora GM, Shanmugasundaram V (2004) Molecular similarity measures. In: Bajorath J (ed) Chemoinformatics: concepts, methods, and tools for drug discovery. Humana Press, Totowa, pp 1\u201350"},{"key":"1002_CR22","doi-asserted-by":"publisher","first-page":"3161","DOI":"10.1016\/j.bmcl.2010.03.096","volume":"20","author":"LJ Chambers","year":"2010","unstructured":"Chambers LJ, Stevens AJ, Moses AP et al (2010) Synthesis and structure-activity relationships of a series of (1H-pyrazol-4-yl)a-cetamide antagonists of the P2X 7 receptor. Bioorg Med Chem Lett 20:3161\u20133164. https:\/\/doi.org\/10.1016\/j.bmcl.2010.03.096","journal-title":"Bioorg Med Chem Lett"},{"key":"1002_CR23","doi-asserted-by":"publisher","first-page":"D1180","DOI":"10.1093\/nar\/gkad1004","volume":"52","author":"B Zdrazil","year":"2024","unstructured":"Zdrazil B, Felix E, Hunter F et al (2024) The ChEMBL Database in 2023: a drug discovery platform spanning multiple bioactivity data types and time periods. Nucleic Acids Res 52:D1180\u2013D1192. https:\/\/doi.org\/10.1093\/nar\/gkad1004","journal-title":"Nucleic Acids Res"},{"key":"1002_CR24","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24119465","author":"F Di Virgilio","year":"2023","unstructured":"Di Virgilio F, Vultaggio-Poma V, Falzoni S, Giuliani AL (2023) The coming of age of the P2X7 receptor in diagnostic medicine. Int J Mol Sci. https:\/\/doi.org\/10.3390\/ijms24119465","journal-title":"Int J Mol Sci"},{"key":"1002_CR25","unstructured":"(2018) RDKit: Open-Source Chemoinformatics"},{"key":"1002_CR26","unstructured":"O\u2019Boyle NM. Noel O\u2019Blog (2019) In: No Charge - Simple Approach Neutralising Charg. Mol. https:\/\/baoilleach.blogspot.com\/2019\/12\/no-charge-simple-approach-to.html. Accessed 1 Oct 2024"},{"key":"1002_CR27","doi-asserted-by":"publisher","first-page":"5080","DOI":"10.1016\/j.bmcl.2010.07.033","volume":"20","author":"MH Abdi","year":"2010","unstructured":"Abdi MH, Beswick PJ, Billinton A et al (2010) Discovery and structure\u2013activity relationships of a series of pyroglutamic acid amide antagonists of the P2X7 receptor. Bioorg Med Chem Lett 20:5080\u20135084. https:\/\/doi.org\/10.1016\/j.bmcl.2010.07.033","journal-title":"Bioorg Med Chem Lett"},{"key":"1002_CR28","unstructured":"Dean DK, Munoz-Muriedas J, Sime M, et al (2010) 5,6,7,8-Tetrahydo[1,2,4]triazolo[4,3-a]pyrazine derivatives as P2X7 modulators"},{"key":"1002_CR29","unstructured":"Chambers LJ, Collis KL, Dean DK, et al (2009) 4-Benzoyl-1-substituted-piperazin-2-one derivatives as P2X7 modulators"}],"container-title":["Journal of Cheminformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13321-025-01002-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13321-025-01002-7\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13321-025-01002-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,24]],"date-time":"2025-04-24T11:55:33Z","timestamp":1745495733000},"score":1,"resource":{"primary":{"URL":"https:\/\/jcheminf.biomedcentral.com\/articles\/10.1186\/s13321-025-01002-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,24]]},"references-count":29,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["1002"],"URL":"https:\/\/doi.org\/10.1186\/s13321-025-01002-7","relation":{},"ISSN":["1758-2946"],"issn-type":[{"value":"1758-2946","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,24]]},"assertion":[{"value":"8 October 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 March 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 April 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"60"}}