{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T21:03:25Z","timestamp":1785359005460,"version":"3.55.0"},"reference-count":35,"publisher":"Wiley","issue":"14","license":[{"start":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T00:00:00Z","timestamp":1784160000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T00:00:00Z","timestamp":1784160000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemMedChem"],"published-print":{"date-parts":[[2026,7,29]]},"abstract":"<jats:p>\n                    High\u2010throughput virtual screening (HTVS) enables rapid exploration of large chemical spaces to identify novel modulators of biologically relevant targets. In this study, we applied a large\u2010scale docking campaign to discover new inhibitors of the human Carbonic Anhydrase isoforms I and II. Starting from library of 28,000 compounds, iterative Glide HTVS, SP, and XP docking against hCA I and hCA II yielded 81 top\u2010ranked compounds for experimental evaluation. Among these, five compounds showed micromolar inhibition of hCA II, and one also inhibited hCA I. X\u2010ray crystallographic studies of two carboxylate\u2010based inhibitors (\n                    <jats:bold>1<\/jats:bold>\n                    and\n                    <jats:bold>2<\/jats:bold>\n                    ) revealed distinct binding modes. Compound\n                    <jats:bold>1<\/jats:bold>\n                    directly coordinates the catalytic zinc ion, whereas compound\n                    <jats:bold>2<\/jats:bold>\n                    adopts two different binding poses: one anchored to the zinc\u2010bound water molecule and another within a surface\u2010accessible pocket near His64. The latter region, which modulates the proton\u2010shuttling mechanism essential for catalysis, represents a less\u2010explored site for inhibitor development. Overall, these findings validate our HTVS workflow and provide a foundation for the structure\u2010guided optimization of carboxylate scaffolds as carbonic anhydrase inhibitors.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.70391","type":"journal-article","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T01:39:19Z","timestamp":1784252359000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Novel Inhibitors of Carbonic Anhydrase I and II Identified by High Throughput Virtual Screening and Validated by X\u2010Ray Crystallography"],"prefix":"10.1002","volume":"21","author":[{"given":"Asher L.","family":"Brandt","sequence":"first","affiliation":[{"name":"Department of Chemistry University of Saint Joseph  West Hartford Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Venditto","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Saint Joseph  West Hartford Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Ferraroni","sequence":"additional","affiliation":[{"name":"Department of Chemistry \u201cUgo Schiff\u201d University of Florence  Sesto Fiorentino 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":"NEUROFARBA Department Sezione di Scienze Farmaceutiche University of Florence  Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1470-7192","authenticated-orcid":false,"given":"Andrea","family":"Angeli","sequence":"additional","affiliation":[{"name":"NEUROFARBA Department Sezione di Scienze Farmaceutiche University of Florence  Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,16]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-0917-9"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.2174\/1568026614666140929124445"},{"key":"e_1_2_8_4_1","first-page":"1380","article-title":"Molecular Docking and Structure\u2010Based Drug Design Strategies","volume":"16","author":"Ferreira L. 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