{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T11:33:03Z","timestamp":1770291183378,"version":"3.49.0"},"reference-count":48,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2018,7,9]],"date-time":"2018-07-09T00:00:00Z","timestamp":1531094400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100004328","name":"Genentech","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004328","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["GM102365"],"award-info":[{"award-number":["GM102365"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["LM05652"],"award-info":[{"award-number":["LM05652"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["HL117798"],"award-info":[{"award-number":["HL117798"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,1,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Motivation<\/jats:title>\n                  <jats:p>Kinases play a significant role in diverse disease signaling pathways and understanding kinase inhibitor selectivity, the tendency of drugs to bind to off-targets, remains a top priority for kinase inhibitor design and clinical safety assessment. Traditional approaches for kinase selectivity analysis using biochemical activity and binding assays are useful but can be costly and are often limited by the kinases that are available. On the other hand, current computational kinase selectivity prediction methods are computational intensive and can rarely achieve sufficient accuracy for large-scale kinome wide inhibitor selectivity profiling.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Here, we present a KinomeFEATURE database for kinase binding site similarity search by comparing protein microenvironments characterized using diverse physiochemical descriptors. Initial selectivity prediction of 15 known kinase inhibitors achieved an &amp;gt;90% accuracy and demonstrated improved performance in comparison to commonly used kinase inhibitor selectivity prediction methods. Additional kinase ATP binding site similarity assessment (120 binding sites) identified 55 kinases with significant promiscuity and revealed unexpected inhibitor cross-activities between PKR and FGFR2 kinases. Kinome-wide selectivity profiling of 11 kinase drug candidates predicted novel as well as experimentally validated off-targets and suggested structural mechanisms of kinase cross-activities. Our study demonstrated potential utilities of our approach for large-scale kinase inhibitor selectivity profiling that could contribute to kinase drug development and safety assessment.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Availability and implementation<\/jats:title>\n                  <jats:p>The KinomeFEATURE database and the associated scripts for performing kinase pocket similarity search can be downloaded from the Stanford SimTK website (https:\/\/simtk.org\/projects\/kdb).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Supplementary information<\/jats:title>\n                  <jats:p>Supplementary data are available at Bioinformatics online.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/bioinformatics\/bty582","type":"journal-article","created":{"date-parts":[[2018,7,6]],"date-time":"2018-07-06T03:44:34Z","timestamp":1530848674000},"page":"235-242","source":"Crossref","is-referenced-by-count":27,"title":["Computational analysis of kinase inhibitor selectivity using structural knowledge"],"prefix":"10.1093","volume":"35","author":[{"given":"Yu-Chen","family":"Lo","sequence":"first","affiliation":[{"name":"Department of Bioengineering, Stanford, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tianyun","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, Stanford, CA, USA"},{"name":"Department of Genetics, Stanford University, Stanford, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kari M","family":"Morrissey","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology, South San Francisco, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Satoko","family":"Kakiuchi-Kiyota","sequence":"additional","affiliation":[{"name":"Department of Safety Assessment, South San Francisco, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adam R","family":"Johnson","sequence":"additional","affiliation":[{"name":"Biochemical and Cellular Pharmacology, South San Francisco, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fabio","family":"Broccatelli","sequence":"additional","affiliation":[{"name":"Department of Drug Metabolism and Pharmacokinetic, Genentech Inc., South San Francisco, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu","family":"Zhong","sequence":"additional","affiliation":[{"name":"Department of Safety Assessment, South San Francisco, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amita","family":"Joshi","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology, South San Francisco, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Russ B","family":"Altman","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, Stanford, CA, USA"},{"name":"Department of Genetics, Stanford University, Stanford, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2018,7,9]]},"reference":[{"key":"2023013107233929200_bty582-B1","doi-asserted-by":"crossref","first-page":"6956","DOI":"10.1158\/0008-5472.CAN-06-4605","article-title":"The RET kinase inhibitor NVP-AST487 blocks growth and calcitonin gene expression through distinct mechanisms in medullary thyroid cancer cells","volume":"67","author":"Akeno-Stuart","year":"2007","journal-title":"Cancer Res."},{"key":"2023013107233929200_bty582-B2","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1038\/nbt.2017","article-title":"Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity","volume":"29","author":"Anastassiadis","year":"2011","journal-title":"Nat. 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