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The catalytic domain of HDAC11 shares low sequence identity with other HDAC isoforms, which makes conventional homology modeling less reliable. AlphaFold is a machine learning approach that can predict the 3D structure of proteins with high accuracy even in absence of similar structures. However, the fact that AlphaFold models are predicted in the absence of small molecules and ions\/cofactors complicates their utilization for drug design. Previously, we optimized an HDAC11 AlphaFold model by adding the catalytic zinc ion and minimization in the presence of reported HDAC11 inhibitors. In the current study, we implement a comparative structure-based virtual screening approach utilizing the previously optimized HDAC11 AlphaFold model to identify novel and selective HDAC11 inhibitors. The stepwise virtual screening approach was successful in identifying a hit that was subsequently tested using an in vitro enzymatic assay. The hit compound showed an IC50 value of 3.5 \u00b5M for HDAC11 and could selectively inhibit HDAC11 over other HDAC subtypes at 10 \u00b5M concentration. In addition, we carried out molecular dynamics simulations to further confirm the binding hypothesis obtained by the docking study. These results reinforce the previously presented AlphaFold optimization approach and confirm the applicability of AlphaFold models in the search for novel inhibitors for drug discovery.<\/jats:p>","DOI":"10.3390\/ijms25021358","type":"journal-article","created":{"date-parts":[[2024,1,22]],"date-time":"2024-01-22T12:01:13Z","timestamp":1705924873000},"page":"1358","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Comparative Structure-Based Virtual Screening Utilizing Optimized AlphaFold Model Identifies Selective HDAC11 Inhibitor"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3242-8514","authenticated-orcid":false,"given":"Fady","family":"Baselious","sequence":"first","affiliation":[{"name":"Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, 06120 Halle (Saale), Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-0611-7365","authenticated-orcid":false,"given":"Sebastian","family":"Hilscher","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, 06120 Halle (Saale), Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dina","family":"Robaa","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, 06120 Halle (Saale), Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2751-3060","authenticated-orcid":false,"given":"Cyril","family":"Barinka","sequence":"additional","affiliation":[{"name":"Institute of Biotechnology of the Czech Academy of Sciences, BIOCEV, 252 50 Vestec, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mike","family":"Schutkowski","sequence":"additional","affiliation":[{"name":"Charles Tanford Protein Center, Department of Enzymology, Institute of Biochemistry and Biotechnology, Martin-Luther-University of Halle-Wittenberg, 06120 Halle (Saale), Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5985-9261","authenticated-orcid":false,"given":"Wolfgang","family":"Sippl","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, 06120 Halle (Saale), Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,1,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1016\/j.sbi.2011.08.004","article-title":"Structure, mechanism, and inhibition of histone deacetylases and related metalloenzymes","volume":"21","author":"Lombardi","year":"2011","journal-title":"Curr. 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