{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T11:07:49Z","timestamp":1790161669628,"version":"4.1.0"},"reference-count":33,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T00:00:00Z","timestamp":1790121600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004166","name":"Medical University of Warsaw","doi-asserted-by":"publisher","award":["16\/F\/MG\/N\/25"],"award-info":[{"award-number":["16\/F\/MG\/N\/25"]}],"id":[{"id":"10.13039\/501100004166","id-type":"DOI","asserted-by":"publisher"}]},{"award":["16\/F\/MG\/N\/25"],"award-info":[{"award-number":["16\/F\/MG\/N\/25"]}],"id":[{"id":"https:\/\/ror.org\/04p2y4s44","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Molecular docking is widely used to predict cyclodextrin host\u2013guest structures, yet its ability to reproduce the directional orientation of asymmetric guests within the \u03b2-cyclodextrin (\u03b2-CD) cavity has rarely been evaluated systematically. Here, 20 crystallographically characterized 1:1 \u03b2-CD complexes containing asymmetric 1,4-disubstituted benzene guests were selected from the Cambridge Structural Database. Each guest was docked into each of 20 experimentally derived \u03b2-CD conformations, yielding 7916 retained poses. Poses reproducing the crystallographic direction of inclusion were classified as Up, whereas the opposite orientation was classified as Down. Across the complete dataset, approximately 26% of poses were Up, with guest-dependent frequencies ranging from 5% to 83%. Importantly, only one \u03b2-CD conformation generated Up poses for all 20 guests, whereas the complete receptor set sampled at least one crystal-consistent pose for every compound. However, GlideScore-based orientation recovery was 65% for Top-1, 95% for Top-2, and 100% for Top-3, demonstrating that successful sampling does not necessarily ensure correct top-ranked prediction. Selected poses were subsequently optimized using dispersion-corrected DFT. DFT-based energetic ranking did not consistently favour the crystallographic orientation and could either decrease or increase guest heavy-atom RMSD. Overall, the results demonstrate that reliable validation of \u03b2-CD docking requires explicit separation of pose generation, pose ranking, energetic refinement, and structural similarity, and support the use of structurally diverse crystal-derived receptor sets to broaden orientational sampling.<\/jats:p>","DOI":"10.3390\/molecules31193379","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T10:17:26Z","timestamp":1790158646000},"page":"3379","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Can Molecular Docking Predict Guest Orientation in \u03b2-Cyclodextrin? A Cross-Docking and DFT Refinement Study"],"prefix":"10.3390","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-3417-518X","authenticated-orcid":false,"given":"Ewa","family":"Napi\u00f3rkowska","sequence":"first","affiliation":[{"name":"Department of Organic and Physical Chemistry, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1 Str., 02-093 Warsaw, Poland"},{"name":"Doctoral School, Medical University of Warsaw, \u017bwirki i Wigury 81 Str., 02-093 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-4485-8903","authenticated-orcid":false,"given":"Konrad Adam","family":"Michalik","sequence":"additional","affiliation":[{"name":"Department of Organic and Physical Chemistry, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1 Str., 02-093 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5302-3797","authenticated-orcid":false,"given":"\u0141ukasz","family":"Szeleszczuk","sequence":"additional","affiliation":[{"name":"Department of Organic and Physical Chemistry, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1 Str., 02-093 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3390\/polysaccharides3010001","article-title":"Cyclodextrins: Structural, Chemical, and Physical Properties, and Applications","volume":"3","author":"Poulson","year":"2022","journal-title":"Polysaccharides"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1016\/j.ijpharm.2017.11.018","article-title":"Cyclodextrins: Structure, Physicochemical Properties and Pharmaceutical Applications","volume":"535","author":"Jansook","year":"2018","journal-title":"Int. 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