{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T18:50:42Z","timestamp":1792003842735,"version":"4.4.0"},"reference-count":54,"publisher":"American Chemical Society (ACS)","issue":"40","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"UKRI","award":["10059436"],"award-info":[{"award-number":["10059436"]}]},{"name":"UKRI","award":["10061100"],"award-info":[{"award-number":["10061100"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Disordered proteins are challenging targets for drug design because they lack well-defined binding pockets. Small molecules can bind them, but when the bound state remains conformationally heterogeneous, these interactions are not readily characterized in terms of conventional binding pockets. Here, we use the concept of binding paths to describe how small molecules interact with disordered proteins. A binding path is a stochastic sequence of transient residue clusters that a ligand engages as it diffuses across a disordered protein, with each cluster forming and breaking up on time scales comparable to the overall residence time. We formalize this approach using a Markov state model (MSM), in which each state corresponds to a set of residues simultaneously contacting the ligand and the transition probabilities capture how the ligand moves between these sets. We apply this framework to the interactions of 10074-G5 with A\u03b242 and of fasudil with \u03b1-synuclein, two disordered proteins associated with Alzheimer\u2019s disease and Parkinson\u2019s disease, respectively. The MSM enables both a dynamic mapping of transient binding sites and a calculation of dissociation constants consistent with experimental measurements. By generalizing the concept of static binding pockets to dynamic binding paths, this approach provides a quantitative framework for characterizing small-molecule binding by disordered proteins and for identifying druggable regions on these challenging targets.<\/jats:p>","DOI":"10.1021\/jacs.6c05891","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T18:01:57Z","timestamp":1790704917000},"page":"42969-42980","source":"Crossref","is-referenced-by-count":0,"title":["Binding\nwithout Docking: Small-Molecule Binding Paths\non Disordered Proteins"],"prefix":"10.1021","volume":"148","author":[{"given":"Adelie","family":"Louet","sequence":"first","affiliation":[{"name":"Max Planck Institute of Biophysics , , ,","place":["Frankfurt am Main, Germany, 60438"]},{"name":"Goethe University Frankfurt , , ,","place":["Frankfurt am Main, Germany, 60438"]},{"name":"University of Cambridge , , ,","place":["Cambridge, U.K., CB2 1EW"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7768-746X","authenticated-orcid":true,"given":"Gerhard","family":"Hummer","sequence":"additional","affiliation":[{"name":"Max Planck Institute of Biophysics , , ,","place":["Frankfurt am Main, Germany, 60438"]},{"name":"Goethe University Frankfurt , , ,","place":["Frankfurt am Main, Germany, 60438"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3616-1610","authenticated-orcid":true,"given":"Michele","family":"Vendruscolo","sequence":"additional","affiliation":[{"name":"University of Cambridge , , ,","place":["Cambridge, U.K., CB2 1EW"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,29]]},"reference":[{"issue":"1","key":"2026101414080943800_cit1","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1038\/nrm3920","article-title":"Intrinsically disordered proteins in cellular signalling\nand regulation","volume":"16","author":"Wright","year":"2015","journal-title":"Nat. Rev. Mol. Cell Biol."},{"issue":"3","key":"2026101414080943800_cit2","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1038\/s41580-023-00673-0","article-title":"The molecular\nbasis for cellular function of intrinsically\ndisordered protein regions","volume":"25","author":"Holehouse","year":"2024","journal-title":"Nat. Rev. Mol. Cell\nBiol."},{"issue":"13","key":"2026101414080943800_cit3","doi-asserted-by":"publisher","first-page":"6589","DOI":"10.1021\/cr400525m","article-title":"Classification\nof intrinsically disordered regions and proteins","volume":"114","author":"Van Der Lee","year":"2014","journal-title":"Chem. Rev."},{"issue":"13","key":"2026101414080943800_cit4","doi-asserted-by":"publisher","first-page":"6561","DOI":"10.1021\/cr400514h","article-title":"Introducing protein\nintrinsic disorder","volume":"114","author":"Habchi","year":"2014","journal-title":"Chem. 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Model."},{"issue":"2","key":"2026101414080943800_cit22","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1021\/ci800324m","article-title":"Identifying\nand characterizing binding sites and assessing druggability","volume":"49","author":"Halgren","year":"2009","journal-title":"J. Chem. Inf. Model."},{"issue":"24","key":"2026101414080943800_cit23","doi-asserted-by":"publisher","first-page":"9629","DOI":"10.1073\/pnas.1121005109","article-title":"Tafamidis, a potent and selective transthyretin kinetic\nstabilizer that inhibits the amyloid cascade","volume":"109","author":"Bulawa","year":"2012","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2026101414080943800_cit24","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1016\/j.sbi.2021.11.009","article-title":"Small molecule protein binding to correct cellular\nfolding or stabilize the native state against misfolding and aggregation","volume":"72","author":"Chiti","year":"2022","journal-title":"Curr. Opin. Struct. Biol."},{"issue":"1","key":"2026101414080943800_cit25","doi-asserted-by":"publisher","first-page":"6390","DOI":"10.1038\/s41467-022-34077-z","article-title":"Small molecules targeting the disordered\ntransactivation domain of the androgen receptor induce the formation\nof collapsed helical states","volume":"13","author":"Zhu","year":"2022","journal-title":"Nat. Commun."},{"issue":"12","key":"2026101414080943800_cit26","doi-asserted-by":"publisher","first-page":"1958","DOI":"10.1038\/s41594-023-01159-5","article-title":"Rational optimization of a transcription factor activation\ndomain inhibitor","volume":"30","author":"Basu","year":"2023","journal-title":"Nat. Struct. Mol. 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Chem."},{"issue":"39","key":"2026101414080943800_cit33","doi-asserted-by":"publisher","first-page":"13692","DOI":"10.1021\/jacs.7b01380","article-title":"A small\nmolecule causes a population shift in the conformational landscape\nof an intrinsically disordered protein","volume":"139","author":"Ban","year":"2017","journal-title":"J. Am.\nChem. Soc."},{"issue":"6","key":"2026101414080943800_cit34","doi-asserted-by":"publisher","first-page":"2501","DOI":"10.1021\/jacs.1c07591","article-title":"Molecular\nbasis of small-molecule binding to \u03b1-synuclein","volume":"144","author":"Robustelli","year":"2022","journal-title":"J. Am. Chem. Soc."},{"issue":"4","key":"2026101414080943800_cit35","doi-asserted-by":"publisher","first-page":"2319","DOI":"10.1021\/jacs.3c11614","article-title":"Picosecond dynamics\nof a small molecule in its bound state with an intrinsically disordered\nprotein","volume":"146","author":"Heller","year":"2024","journal-title":"J. Am. Chem. Soc."},{"issue":"14","key":"2026101414080943800_cit36","doi-asserted-by":"publisher","first-page":"4711","DOI":"10.1021\/acs.jctc.3c00224","article-title":"Clustering heterogeneous conformational ensembles of\nintrinsically disordered proteins with t-distributed stochastic neighbor\nembedding","volume":"19","author":"Appadurai","year":"2023","journal-title":"J. Chem. Theory Comput."},{"issue":"45","key":"2026101414080943800_cit37","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abb5924","article-title":"Small-molecule sequestration\nof amyloid-\u03b2 as a drug discovery strategy for Alzheimer\u2019s\ndisease","volume":"6","author":"Heller","year":"2020","journal-title":"Sci. Adv."},{"issue":"12","key":"2026101414080943800_cit38","doi-asserted-by":"publisher","first-page":"1738","DOI":"10.1021\/acschemneuro.2c00116","article-title":"A small molecule stabilizes the disordered native state\nof the Alzheimer\u2019s A\u03b2 peptide","volume":"13","author":"Lohr","year":"2022","journal-title":"ACS Chem. Neurosci"},{"issue":"3","key":"2026101414080943800_cit39","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1002\/wcms.1167","article-title":"Insights into the binding of intrinsically\ndisordered\nproteins from molecular dynamics simulation","volume":"4","author":"Baker","year":"2014","journal-title":"Wiley Interdiscip. Rev. Comput. Mol. Sci."},{"issue":"10","key":"2026101414080943800_cit40","doi-asserted-by":"publisher","first-page":"5003","DOI":"10.1021\/acs.jcim.0c00381","article-title":"Small molecule modulation of intrinsically\ndisordered proteins using molecular dynamics simulations","volume":"60","author":"Herrera-Nieto","year":"2020","journal-title":"J. Chem. Inf. Model."},{"issue":"23","key":"2026101414080943800_cit41","doi-asserted-by":"publisher","first-page":"235101","DOI":"10.1063\/1.5129150","article-title":"Transition path dynamics in the binding\nof intrinsically\ndisordered proteins: A simulation study","volume":"151","author":"Ozmaian","year":"2019","journal-title":"J.\nChem. Phys."},{"issue":"17","key":"2026101414080943800_cit42","doi-asserted-by":"publisher","first-page":"174105","DOI":"10.1063\/1.3565032","article-title":"Markov models\nof molecular kinetics: Generation and validation","volume":"134","author":"Prinz","year":"2011","journal-title":"J. Chem. 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U.S.A."},{"issue":"1","key":"2026101414080943800_cit46","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1038\/s41467-017-02388-1","article-title":"VAMPNets for\ndeep learning of molecular kinetics","volume":"9","author":"Mardt","year":"2018","journal-title":"Nat. Commun."},{"key":"2026101414080943800_cit47","volume-title":"Stochastic\nProcesses in Physics and Chemistry","author":"Van Kampen","year":"1992"},{"issue":"10","key":"2026101414080943800_cit48","doi-asserted-by":"publisher","first-page":"P10008","DOI":"10.1088\/1742-5468\/2008\/10\/P10008","article-title":"Fast unfolding of communities\nin large networks","volume":"2008","author":"Blondel","year":"2008","journal-title":"J. Stat. Mech. Theory Exp."},{"issue":"21","key":"2026101414080943800_cit49","doi-asserted-by":"publisher","first-page":"E4758","DOI":"10.1073\/pnas.1800690115","article-title":"Developing\na molecular dynamics force\nfield for both folded and disordered protein states","volume":"115","author":"Robustelli","year":"2018","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"issue":"24","key":"2026101414080943800_cit50","doi-asserted-by":"publisher","first-page":"10890","DOI":"10.1073\/pnas.1003962107","article-title":"Protein folded states are kinetic\nhubs","volume":"107","author":"Bowman","year":"2010","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"issue":"10","key":"2026101414080943800_cit51","doi-asserted-by":"publisher","first-page":"3810","DOI":"10.1021\/ct300077q","article-title":"Identifying metastable\nstates of folding proteins","volume":"8","author":"Jain","year":"2012","journal-title":"J. Chem. Theory\nComput."},{"issue":"43","key":"2026101414080943800_cit52","doi-asserted-by":"publisher","first-page":"16092","DOI":"10.1021\/ja403147m","article-title":"Dynamics of\nan intrinsically disordered\nprotein reveal metastable conformations that potentially seed aggregation","volume":"135","author":"Qiao","year":"2013","journal-title":"J. Am. Chem. Soc."},{"issue":"10","key":"2026101414080943800_cit53","doi-asserted-by":"publisher","first-page":"2319","DOI":"10.1002\/jcc.21787","article-title":"MDAnalysis:\na toolkit for the analysis of molecular dynamics simulations","volume":"32","author":"Michaud-Agrawal","year":"2011","journal-title":"J. Comput. Chem."},{"key":"2026101414080943800_cit54","volume-title":"Exploring Network Structure,\nDynamics, and Function Using NetworkX","author":"Hagberg","year":"2007"}],"container-title":["Journal of the American Chemical Society"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/jacs.6c05891","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/jacsat\/article-pdf\/148\/40\/42969\/68701577\/jacs.6c05891.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/jacsat\/article-pdf\/148\/40\/42969\/68701577\/jacs.6c05891.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T18:30:20Z","timestamp":1792002620000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/jacsat\/article\/148\/40\/42969\/5441767\/Binding-without-Docking-Small-Molecule-Binding"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,29]]},"references-count":54,"journal-issue":{"issue":"40","published-online":{"date-parts":[[2026,9,29]]},"published-print":{"date-parts":[[2026,10,14]]}},"URL":"https:\/\/doi.org\/10.1021\/jacs.6c05891","relation":{},"ISSN":["0002-7863","1520-5126"],"issn-type":[{"value":"0002-7863","type":"print"},{"value":"1520-5126","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,29]]}}}