{"id":32455,"date":"2026-01-21T17:02:00","date_gmt":"2026-01-21T17:02:00","guid":{"rendered":"https:\/\/lamarr-institute.org\/publication\/combining-a-chemical-language-model-and-the-structure-activity-relationship-matrix-formalism-for-generative-design-of-potent-compounds-with-core-structure-and-substituent-modifications\/"},"modified":"2026-06-08T13:20:37","modified_gmt":"2026-06-08T13:20:37","slug":"combining-a-chemical-language-model-and-the-structure-activity-relationship-matrix-formalism-for-generative-design-of-potent-compounds-with-core-structure-and-substituent-modifications","status":"publish","type":"publication","link":"https:\/\/lamarr-institute.org\/de\/publication\/combining-a-chemical-language-model-and-the-structure-activity-relationship-matrix-formalism-for-generative-design-of-potent-compounds-with-core-structure-and-substituent-modifications\/","title":{"rendered":"Combining a Chemical Language Model and the Structure\u2013Activity Relationship Matrix Formalism for Generative Design of Potent Compounds with Core Structure and Substituent Modifications"},"content":{"rendered":"<p>In medicinal chemistry, compound optimization relies on the generation of analogue series ({AS}) for exploring structure\u2013activity relationships ({SARs}). Potency progression is a critical criterion for advancing {AS}. During optimization, a key question is which analogues to synthesize next. We introduce a new computational methodology for the extension of {AS} with potent compounds containing both core structure and substituent modifications at multiple sites, which has been reported for the first time. The approach combines a transformer chemical language model ({CLM}) with a {SAR} matrix ({SARM}) methodology that identifies and organizes structurally related {AS}. Therefore, the {SARM} approach was expanded to cover multisite {AS}. Consensus series extracted from {SARMs} representing a potency gradient served as input for {CLM} training to extend test {AS} with potent analogues. Different model variants were derived and investigated. Both general and fine-tuned models correctly predicted known potent analogues at high positions in probability-based compound rankings and chemically diversified {AS} through core structure modifications of the generated candidate compounds and substituent replacements at multiple sites.<\/p>\n","protected":false},"excerpt":{"rendered":"<p>In medicinal chemistry, compound optimization relies on the generation of analogue series ({AS}) for exploring structure\u2013activity relationships ({SARs}). Potency progression is a critical criterion for advancing {AS}. During optimization, a key question is which analogues to synthesize next. We introduce a new computational methodology for the extension of {AS} with potent compounds containing both core structure and substituent modifications at multiple sites, which has been reported for the first time. [&hellip;]<\/p>\n","protected":false},"author":12,"featured_media":0,"template":"","meta":{"_acf_changed":false,"footnotes":""},"publication-type":[30],"class_list":["post-32455","publication","type-publication","status-publish","hentry","publication-type-article"],"acf":[],"publishpress_future_workflow_manual_trigger":{"enabledWorkflows":[]},"_links":{"self":[{"href":"https:\/\/lamarr-institute.org\/de\/wp-json\/wp\/v2\/publication\/32455","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/lamarr-institute.org\/de\/wp-json\/wp\/v2\/publication"}],"about":[{"href":"https:\/\/lamarr-institute.org\/de\/wp-json\/wp\/v2\/types\/publication"}],"author":[{"embeddable":true,"href":"https:\/\/lamarr-institute.org\/de\/wp-json\/wp\/v2\/users\/12"}],"version-history":[{"count":0,"href":"https:\/\/lamarr-institute.org\/de\/wp-json\/wp\/v2\/publication\/32455\/revisions"}],"wp:attachment":[{"href":"https:\/\/lamarr-institute.org\/de\/wp-json\/wp\/v2\/media?parent=32455"}],"wp:term":[{"taxonomy":"publication-type","embeddable":true,"href":"https:\/\/lamarr-institute.org\/de\/wp-json\/wp\/v2\/publication-type?post=32455"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}