{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T11:15:46Z","timestamp":1788002146842,"version":"build-2784847793"},"reference-count":45,"publisher":"American Chemical Society (ACS)","issue":"14","license":[{"start":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T00:00:00Z","timestamp":1783641600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,7,27]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>In recent years make-on-demand compound libraries (so-called Chemical Spaces) have gained more and more interest in pharmaceutical industry. Compound vendors promise cheap compounds, fast delivery, high synthetical accessibility and a large pool of novel chemical matter, fulfilling the requirements of fast Design-Make-Test cycles. Searching in ultralarge Chemical Spaces with known 2D similarity metrics, like fingerprint-based Tanimoto, substructure, or pharmacophore similarity searches, contains pitfalls due to the representation of molecules as synthons with connectivity rules. Applied to a set of almost 3000 drug-relevant queries we analyzed the ability of similarity search methods to retrieve analog compounds from Chemical Spaces, and how to best approach typical use cases in early phase drug discovery. Distinct characteristics of each similarity metric suggest orthogonal complementarity, enabling a versatile framework to diverse challenges present in hit discovery and lead expansion campaigns. Our investigations resulted in formulating practical considerations and guidelines for interpreting the scores including recommendations for thresholds for each similarity metric.<\/jats:p>","DOI":"10.1021\/acs.jcim.6c01496","type":"journal-article","created":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T13:11:36Z","timestamp":1783689096000},"page":"8251-8268","source":"Crossref","is-referenced-by-count":1,"title":["Strategies for\nIdentifying Molecules of Interest in\nLarge Chemical Spaces"],"prefix":"10.1021","volume":"66","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5087-8730","authenticated-orcid":true,"given":"Raphael","family":"Klein","sequence":"first","affiliation":[{"name":"BioSolveIT GmbH , An der Ziegelei 79 , ,","place":["Sankt Augustin, Germany, 53757"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sascha","family":"Jung","sequence":"additional","affiliation":[{"name":"BioSolveIT GmbH , An der Ziegelei 79 , ,","place":["Sankt Augustin, Germany, 53757"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Neumann","sequence":"additional","affiliation":[{"name":"BioSolveIT GmbH , An der Ziegelei 79 , ,","place":["Sankt Augustin, Germany, 53757"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehran","family":"Jalaie","sequence":"additional","affiliation":[{"name":"Pfizer Inc , , 10555 Science Center Dr , , ,","place":["San Diego, California, United States, 92121"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan M.","family":"Mathiowetz","sequence":"additional","affiliation":[{"name":"Pfizer Inc , , 1 Portland St , , ,","place":["Cambridge, Massachusetts, United States, 02139"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7025-3287","authenticated-orcid":true,"given":"Markus","family":"Boehm","sequence":"additional","affiliation":[{"name":"Pfizer Inc , , 1 Portland St , , ,","place":["Cambridge, Massachusetts, United States, 02139"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,10]]},"reference":[{"issue":"5","key":"2026072709090918900_cit1","doi-asserted-by":"publisher","first-page":"1148","DOI":"10.1016\/j.drudis.2019.02.013","article-title":"The next Level\nin Chemical Space Navigation: Going\nFar beyond Enumerable Compound Libraries","volume":"24","author":"Hoffmann","year":"2019","journal-title":"Drug\nDiscovery Today"},{"issue":"9","key":"2026072709090918900_cit2","doi-asserted-by":"publisher","first-page":"2021","DOI":"10.1021\/acs.jcim.2c00224","article-title":"Exploration of Ultralarge\nCompound Collections for Drug Discovery","volume":"62","author":"Warr","year":"2022","journal-title":"J.\nChem. 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