{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T16:07:15Z","timestamp":1791734835165,"version":"4.3.4"},"reference-count":57,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,7,5]],"date-time":"2025-07-05T00:00:00Z","timestamp":1751673600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: Human carbonic anhydrases (hCAs) are metalloenzymes involved in essential physiological processes, and their selective inhibition holds therapeutic potential across a wide range of disorders. However, the high degree of structural similarity among isoforms poses a significant challenge for the design of selective inhibitors. In this work, we present a machine learning (ML)-based platform for the isoform-specific prediction and profiling of small molecules targeting hCA I, II, IX, and XII. Methods: By integrating four molecular representations with four ML algorithms, we built 64 classification models, each extensively optimized and validated. The best-performing models for each isoform were applied in a virtual screening campaign for ~2 million compounds. Results: Following a multi-step refinement process, 12 candidates were identified, purchased, and experimentally tested. Several compounds showed potent inhibitory activity in the nanomolar to submicromolar range, with selectivity profiles across the isoforms. To gain mechanistic insights, SHAP-based feature importance analysis and molecular docking supported by molecular dynamics simulations were employed, highlighting the structural determinants of the predicted activity. Conclusions: This study demonstrates the effectiveness of integrating ML, cheminformatics, and experimental validation to accelerate the discovery of selective carbonic anhydrase inhibitors and provides a generalizable framework for activity profiling across enzyme isoforms.<\/jats:p>","DOI":"10.3390\/ph18071007","type":"journal-article","created":{"date-parts":[[2025,7,7]],"date-time":"2025-07-07T02:53:07Z","timestamp":1751856787000},"page":"1007","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["A Machine Learning Platform for Isoform-Specific Identification and Profiling of Human Carbonic Anhydrase Inhibitors"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-5062-4590","authenticated-orcid":false,"given":"Lisa","family":"Piazza","sequence":"first","affiliation":[{"name":"Department of Pharmacy, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6727-5816","authenticated-orcid":false,"given":"Miriana","family":"Di Stefano","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-6947-7903","authenticated-orcid":false,"given":"Clarissa","family":"Poles","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine, 80078 Naples, Italy"},{"name":"Genomics and Experimental Medicine Program, Scuola Superiore Meridionale (SSM, School of Advanced Studies), 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4336-4344","authenticated-orcid":false,"given":"Giulia","family":"Bononi","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulio","family":"Poli","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-9109-030X","authenticated-orcid":false,"given":"Gioele","family":"Renzi","sequence":"additional","affiliation":[{"name":"Department of Neurofarba, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, Sesto Fiorentino, 50019 Firenze, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1959-5839","authenticated-orcid":false,"given":"Salvatore","family":"Galati","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5959-016X","authenticated-orcid":false,"given":"Antonio","family":"Giordano","sequence":"additional","affiliation":[{"name":"Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Macchia","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1141-6146","authenticated-orcid":false,"given":"Fabrizio","family":"Carta","sequence":"additional","affiliation":[{"name":"Department of Neurofarba, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, Sesto Fiorentino, 50019 Firenze, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4262-0323","authenticated-orcid":false,"given":"Claudiu T.","family":"Supuran","sequence":"additional","affiliation":[{"name":"Department of Neurofarba, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, Sesto Fiorentino, 50019 Firenze, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6205-4069","authenticated-orcid":false,"given":"Tiziano","family":"Tuccinardi","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, 56126 Pisa, Italy"},{"name":"Consorzio Interuniversitario Nazionale per la Scienza e Tecnologia dei Materiali (INSTM), 50121 Firenze, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"100004","DOI":"10.1124\/pharmrev.124.001125","article-title":"Multi- and Polypharmacology of Carbonic Anhydrase Inhibitors","volume":"77","author":"Supuran","year":"2025","journal-title":"Pharmacol. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Supuran, C.T. (2023). 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