{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T04:04:24Z","timestamp":1789358664953,"version":"build-2803163510"},"reference-count":76,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,7,5]],"date-time":"2026-07-05T00:00:00Z","timestamp":1783209600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,7,5]],"date-time":"2026-07-05T00:00:00Z","timestamp":1783209600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Applied Toxicology"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    In silico methods such as quantitative structure\u2013activity relationships (QSARs) are widely used in drug development for prescreening of \u2018drug\u2010likeness\u2019. Most of these tools correlate biological properties to two\u2010dimensional (2D) descriptors, which do not account for important structural elements pertaining to three\u2010dimensional (3D) geometry and shape. To address this, we have developed the \u2018EigenValue Analysis\u2019 (EVANS) methodology, a variant of QSAR in which descriptors are computed as a hybrid of 2D physicochemical properties and 3D geometry. Having previously applied EVANS to build QSAR models for several datasets across a range of endpoints relevant to drug discovery and development, we now apply EVANS to build QSAR models for transdermal permeation. A high\u2010quality dataset of 187 compounds with human skin permeability data was carefully curated using strict exclusion criteria. The EVANS methodology was applied and QSAR models were built correlating the calculated hybrid eigenvalues to the logarithmic skin permeability coefficient (log\n                    <jats:italic>K<\/jats:italic>\n                    <jats:sub>p<\/jats:sub>\n                    ) using multiple linear regression (MLR), random forest (RF) and support vector machine (SVM) algorithms. The SVM\u2010based model built using five descriptors demonstrated the best performance. Further external validation was performed by retrieving 52 chemicals from the SkinPiX database, providing additional insight into the model's generalisability. The model was subsequently used to make predictions for two untested compounds (4\u2010methylumbelliferone and levofloxacin), and experimental validation following the protocol described under OECD test no. 428 confirmed that EVANS model predictions closely matched observed values and outperformed established models including those of Potts and Guy, Frasch and the Modified Robinson model. Thus, we present a robust model for prediction of transdermal permeation, along with a QSAR methodology that has been extensively benchmarked and is experimentally validated. The EVANS methodology is open source, with codes and documentation freely available at\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/github.com\/anish19292\/Eigenvalue_analysis\">https:\/\/github.com\/anish19292\/Eigenvalue_analysis<\/jats:ext-link>\n                    .\n                  <\/jats:p>","DOI":"10.1002\/jat.70333","type":"journal-article","created":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T00:57:54Z","timestamp":1783299474000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Development and OECD\u2010Guided Experimental Validation of Eigenvalue\u2010Based QSAR Models for Skin Permeation"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7473-0108","authenticated-orcid":false,"given":"Anish","family":"Gomatam","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry Bombay College of Pharmacy  Mumbai India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6818-039X","authenticated-orcid":false,"given":"Manu","family":"Mathew","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics Apollo Main Hospital  Chennai India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8621-6106","authenticated-orcid":false,"given":"Jeffrey Pradeep","family":"Raj","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Department of Pharmacology, Kasturba Medical College Manipal Academy of Higher Education  Manipal India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kavita","family":"Raikuvar","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry Bombay College of Pharmacy  Mumbai India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saurabh","family":"Katawale","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics SVKM's Dr. Bhanuben Nanavati College of Pharmacy  Mumbai India"},{"name":"Department of Pharmaceutics Bombay College of Pharmacy  Mumbai India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hemali","family":"Savla","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics Bombay College of Pharmacy  Mumbai India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krishna","family":"Iyer","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry Bombay College of Pharmacy  Mumbai India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evans","family":"Coutinho","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry Bombay College of Pharmacy  Mumbai India"},{"name":"St. John Institute of Pharmacy and Research  Palghar India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,5]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1023\/a:1016031629845"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/jps.20773"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jcim.5b00206"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2014.12.013"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11095\u2010015\u20101629\u2010y"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky318"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkae303"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.2174\/092986712803306358"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.envint.2016.05.025"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.20290"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41597\u2010024\u201003026\u20104"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.dib.2022.108242"},{"key":"e_1_2_9_14_1","volume-title":"Stereoselective Pharmacokinetics and Placental Transfer of Fluoxetine and Norfluoxetine in Pregnant Sheep Under Steady\u2010State Conditions","author":"Chien C.","year":"2004"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1021\/ci200211n"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1021\/ci900115y"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep42717"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.114.059857"},{"key":"e_1_2_9_19_1","volume-title":"Principles of Route to Route Extrapolation for Risk Assessment","author":"Flynn G. 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