{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T11:09:21Z","timestamp":1775560161726,"version":"3.50.1"},"reference-count":61,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,9,25]],"date-time":"2025-09-25T00:00:00Z","timestamp":1758758400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,9,25]],"date-time":"2025-09-25T00:00:00Z","timestamp":1758758400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["421152132"],"award-info":[{"award-number":["421152132"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002347","name":"Bundesministerium f\u00fcr Bildung und Forschung","doi-asserted-by":"publisher","award":["ScaDS.AI"],"award-info":[{"award-number":["ScaDS.AI"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000864","name":"Michael J. Fox Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100000864","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Critical Assessment of Computational Hit-finding Experiments"},{"name":"The Structural Genomics Consortium"},{"DOI":"10.13039\/501100008678","name":"Universit\u00e4t Leipzig","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100008678","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Cheminform"],"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>\n                      In this study, we present a pipeline for identifying novel ligands targeting the Tryptophan-Aspartate-Repeat domain 40 (WDR40) of Leucine-Rich Repeat Kinase 2 (LRRK2), a protein associated with Parkinson\u2019s disease, as part of the first Critical Assessment of Computational Hit-finding Experiments (CACHE) challenge, a blind benchmark experiment for drug discovery. Mutations in this protein are the most common genetic cause of familial Parkinson\u2019s disease, yet this target remains understudied. We conducted an ultra-large library screening (ULLS) of the Enamine REAL space using a newly developed evolutionary algorithm, RosettaEvolutionaryLigand (REvoLd), which allows for efficient screening of combinatorial compound libraries. The protocol involved refining the target structure with molecular dynamic simulations, identifying a binding site via blind-docking, and optimizing compounds through REvoLd, culminating in a manual selection amongst the top-scoring REvoLd hits. A single binder molecule was identified that derived from the combination of two Enamine building blocks. In the second round, derivatives of the hit compound were used as input for REvoLd to further sample within the Enamine REAL space. Ultimately, a total of five molecules were identified, from which three show a measurable dissociation constant K\n                      <jats:inline-formula>\n                        <jats:alternatives>\n                          <jats:tex-math>$$_D$$<\/jats:tex-math>\n                          <mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\">\n                            <mml:mmultiscripts>\n                              <mml:mrow\/>\n                              <mml:mi>D<\/mml:mi>\n                              <mml:mrow\/>\n                            <\/mml:mmultiscripts>\n                          <\/mml:math>\n                        <\/jats:alternatives>\n                      <\/jats:inline-formula>\n                      value better than 150\u00a0\n                      <jats:inline-formula>\n                        <jats:alternatives>\n                          <jats:tex-math>$$\\upmu$$<\/jats:tex-math>\n                          <mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\">\n                            <mml:mi>\u03bc<\/mml:mi>\n                          <\/mml:math>\n                        <\/jats:alternatives>\n                      <\/jats:inline-formula>\n                      \u03bcm, showcasing the effectiveness of this approach. However, it also highlighted shortcomings, such as the preference for nitrogen-rich rings in the RosettaLigand scoring function.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Scientific contribution<\/jats:title>\n                    <jats:p>We introduce the first real-world application for REvoLd, an evolutionary docking algorithm enabling efficient ultra-large library screening for flexible protein targets. Our approach identified novel binders for the WDR40 domain of LRRK2 within the CACHE challenge #1, representing the first prospective validation of REvoLd. Here, we present a preparation pipeline to allow exploration of a large protein pocket with unspecific binding areas, and unlike prior brute-force docking efforts, our method integrates receptor flexibility and combinatorial chemistry optimization.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical Abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1186\/s13321-025-01084-3","type":"journal-article","created":{"date-parts":[[2025,9,25]],"date-time":"2025-09-25T15:20:13Z","timestamp":1758813613000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Cache: Utilizing ultra-large library screening in Rosetta to identify novel binders of the WD-repeat domain of Leucine-Rich Repeat Kinase 2"],"prefix":"10.1186","volume":"17","author":[{"given":"Fabian","family":"Liessmann","sequence":"first","affiliation":[]},{"given":"Paul","family":"Eisenhuth","sequence":"additional","affiliation":[]},{"given":"Alexander","family":"F\u00fcrll","sequence":"additional","affiliation":[]},{"given":"Oanh","family":"Vu","sequence":"additional","affiliation":[]},{"given":"Rocco","family":"Moretti","sequence":"additional","affiliation":[]},{"given":"Jens","family":"Meiler","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2025,9,25]]},"reference":[{"key":"1084_CR1","doi-asserted-by":"publisher","first-page":"102578","DOI":"10.1016\/j.sbi.2023.102578","volume":"80","author":"M Korn","year":"2023","unstructured":"Korn M, Ehrt C, Ruggiu F et al (2023) Navigating large chemical spaces in early-phase drug discovery. Curr Opin Struct Biol 80:102578","journal-title":"Curr Opin Struct Biol"},{"issue":"9","key":"1084_CR2","doi-asserted-by":"publisher","first-page":"2021","DOI":"10.1021\/acs.jcim.2c00224","volume":"62","author":"WA Warr","year":"2022","unstructured":"Warr WA, Nicklaus MC, Nicolaou CA et al (2022) Exploration of ultralarge compound collections for drug discovery. J Chem Inf Model 62(9):2021\u20132034","journal-title":"J Chem Inf Model"},{"issue":"10","key":"1084_CR3","doi-asserted-by":"publisher","first-page":"4799","DOI":"10.1038\/s41596-021-00597-z","volume":"16","author":"BJ Bender","year":"2021","unstructured":"Bender BJ, Gahbauer S, Luttens A et al (2021) A practical guide to large-scale docking. Nat Protoc 16(10):4799\u20134832","journal-title":"Nat Protoc"},{"issue":"6","key":"1084_CR4","doi-asserted-by":"publisher","first-page":"939","DOI":"10.1021\/acscentsci.0c00229","volume":"6","author":"F Gentile","year":"2020","unstructured":"Gentile F, Agrawal V, Hsing M et al (2020) Deep docking: a deep learning platform for augmentation of structure based drug discovery. ACS Cent Sci 6(6):939\u2013949","journal-title":"ACS Cent Sci"},{"issue":"15","key":"1084_CR5","doi-asserted-by":"publisher","first-page":"10241","DOI":"10.1021\/acs.jmedchem.3c00128","volume":"66","author":"A Gryniukova","year":"2023","unstructured":"Gryniukova A, Kaiser F, Myziuk I et al (2023) Ai-powered virtual screening of large compound libraries leads to the discovery of novel inhibitors of sirtuin-1. J Med Chem 66(15):10241\u201310251","journal-title":"J Med Chem"},{"issue":"7893","key":"1084_CR6","doi-asserted-by":"publisher","first-page":"452","DOI":"10.1038\/s41586-021-04220-9","volume":"601","author":"AA Sadybekov","year":"2022","unstructured":"Sadybekov AA, Sadybekov AV, Liu Y et al (2022) Synthon-based ligand discovery in virtual libraries of over 11 billion compounds. Nature 601(7893):452\u2013459","journal-title":"Nature"},{"issue":"1","key":"1084_CR7","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1002\/(SICI)1098-1128(199601)16:1<3::AID-MED1>3.0.CO;2-6","volume":"16","author":"RS Bohacek","year":"1996","unstructured":"Bohacek RS, McMartin C, Guida WC (1996) The art and practice of structure-based drug design: a molecular modeling perspective. Med Res Rev 16(1):3\u201350","journal-title":"Med Res Rev"},{"issue":"3","key":"1084_CR8","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1021\/acs.jcim.1c01378","volume":"62","author":"L Bellmann","year":"2022","unstructured":"Bellmann L, Penner P, Gastreich M et al (2022) Comparison of combinatorial fragment spaces and its application to ultralarge make-on-demand compound catalogs. J Chem Inf Model 62(3):553\u2013566","journal-title":"J Chem Inf Model"},{"issue":"11","key":"1084_CR9","doi-asserted-by":"publisher","first-page":"101681","DOI":"10.1016\/j.isci.2020.101681","volume":"23","author":"OO Grygorenko","year":"2020","unstructured":"Grygorenko OO, Radchenko DS, Dziuba I et al (2020) Generating multibillion chemical space of readily accessible screening compounds. Iscience 23(11):101681","journal-title":"Iscience"},{"issue":"6","key":"1084_CR10","doi-asserted-by":"publisher","first-page":"712","DOI":"10.1038\/s41589-022-01234-w","volume":"19","author":"J Lyu","year":"2023","unstructured":"Lyu J, Irwin JJ, Shoichet BK (2023) Modeling the expansion of virtual screening libraries. Nat Chem Biol 19(6):712\u2013718","journal-title":"Nat Chem Biol"},{"issue":"7890","key":"1084_CR11","doi-asserted-by":"publisher","first-page":"759","DOI":"10.1038\/s41586-021-04175-x","volume":"600","author":"A Alon","year":"2021","unstructured":"Alon A, Lyu J, Braz JM et al (2021) Structures of the $$\\sigma$$2 receptor enable docking for bioactive ligand discovery. Nature 600(7890):759\u2013764","journal-title":"Nature"},{"issue":"7743","key":"1084_CR12","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1038\/s41586-019-0917-9","volume":"566","author":"J Lyu","year":"2019","unstructured":"Lyu J, Wang S, Balius TE et al (2019) Ultra-large library docking for discovering new chemotypes. Nature 566(7743):224\u2013229","journal-title":"Nature"},{"issue":"12","key":"1084_CR13","doi-asserted-by":"publisher","first-page":"7785","DOI":"10.1021\/acs.jmedchem.2c02120","volume":"66","author":"I Singh","year":"2023","unstructured":"Singh I, Li F, Fink EA et al (2023) Structure-based discovery of inhibitors of the sars-cov-2 nsp14 n7-methyltransferase. J Med Chem 66(12):7785\u20137803","journal-title":"J Med Chem"},{"key":"1084_CR14","unstructured":"Eisenhuth P, Liessmann F, Moretti R, et\u00a0al (2024) Revold: Ultra-large library screening with an evolutionary algorithm in rosetta. arXiv preprint arXiv:2404.17329"},{"issue":"7","key":"1084_CR15","doi-asserted-by":"publisher","first-page":"e0132508","DOI":"10.1371\/journal.pone.0132508","volume":"10","author":"S DeLuca","year":"2015","unstructured":"DeLuca S, Khar K, Meiler J (2015) Fully flexible docking of medium sized ligand libraries with Rosettaligand. PLoS ONE 10(7):e0132508","journal-title":"PLoS ONE"},{"issue":"3","key":"1084_CR16","doi-asserted-by":"publisher","first-page":"538","DOI":"10.1002\/prot.21086","volume":"65","author":"J Meiler","year":"2006","unstructured":"Meiler J, Baker D (2006) Rosettaligand: protein-small molecule docking with full side-chain flexibility. Proteins Struct Funct Bioinform 65(3):538\u2013548","journal-title":"Proteins Struct Funct Bioinform"},{"key":"1084_CR17","doi-asserted-by":"crossref","unstructured":"Moult J, Pedersen JT, Judson R, Fidelis K et\u00a0al (1995) A large-scale experiment to assess protein structure prediction methods. In: Proteins: structure, function, and bioinformatics, vol 23, no 3, ii-iv","DOI":"10.1002\/prot.340230303"},{"issue":"1","key":"1084_CR18","doi-asserted-by":"publisher","first-page":"19585","DOI":"10.1038\/s41598-019-55069-y","volume":"9","author":"S Chiba","year":"2019","unstructured":"Chiba S, Ohue M, Gryniukova A et al (2019) A prospective compound screening contest identified broader inhibitors for sirtuin 1. Sci Rep 9(1):19585","journal-title":"Sci Rep"},{"key":"1084_CR19","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s10822-017-0088-4","volume":"32","author":"Z Gaieb","year":"2018","unstructured":"Gaieb Z, Liu S, Gathiaka S et al (2018) D3r grand challenge 2: blind prediction of protein-ligand poses, affinity rankings, and relative binding free energies. J Comput Aided Mol Des 32:1\u201320","journal-title":"J Comput Aided Mol Des"},{"issue":"4","key":"1084_CR20","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1038\/s41570-022-00363-z","volume":"6","author":"S Ackloo","year":"2022","unstructured":"Ackloo S, Al-Awar R, Amaro RE et al (2022) Cache (critical assessment of computational hit-finding experiments): a public-private partnership benchmarking initiative to enable the development of computational methods for hit-finding. Nat Rev Chem 6(4):287\u2013295","journal-title":"Nat Rev Chem"},{"issue":"12","key":"1084_CR21","doi-asserted-by":"publisher","first-page":"791","DOI":"10.1038\/nrn2935","volume":"11","author":"MR Cookson","year":"2010","unstructured":"Cookson MR (2010) The role of leucine-rich repeat kinase 2 (lrrk2) in Parkinson\u2019s disease. Nat Rev Neurosci 11(12):791\u2013797","journal-title":"Nat Rev Neurosci"},{"issue":"7837","key":"1084_CR22","doi-asserted-by":"publisher","first-page":"344","DOI":"10.1038\/s41586-020-2673-2","volume":"588","author":"C Deniston","year":"2020","unstructured":"Deniston C, Salogiannis J, Mathea S et al (2020) Structure of lrrk2 in Parkinson\u2019s disease and model for microtubule interaction. Nature 588(7837):344\u2013349","journal-title":"Nature"},{"issue":"11","key":"1084_CR23","doi-asserted-by":"publisher","first-page":"773","DOI":"10.1038\/nrd.2017.179","volume":"16","author":"M Schapira","year":"2017","unstructured":"Schapira M, Tyers M, Torrent M et al (2017) Wd40 repeat domain proteins: a novel target class? Nat Rev Drug Discov 16(11):773\u2013786","journal-title":"Nat Rev Drug Discov"},{"issue":"12","key":"1084_CR24","doi-asserted-by":"publisher","first-page":"1415","DOI":"10.1517\/13543776.2012.729041","volume":"22","author":"X Deng","year":"2012","unstructured":"Deng X, Choi HG, Buhrlage SJ et al (2012) Leucine-rich repeat kinase 2 inhibitors: a patent review (2006\u20132011). Expert Opin Ther Pat 22(12):1415\u20131426","journal-title":"Expert Opin Ther Pat"},{"issue":"2","key":"1084_CR25","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1002\/mds.26075","volume":"30","author":"AB West","year":"2015","unstructured":"West AB (2015) Ten years and counting: moving leucine-rich repeat kinase 2 inhibitors to the clinic. Mov Disord 30(2):180\u2013189","journal-title":"Mov Disord"},{"issue":"13","key":"1084_CR26","doi-asserted-by":"publisher","first-page":"3519","DOI":"10.1016\/j.cell.2021.05.004","volume":"184","author":"A Myasnikov","year":"2021","unstructured":"Myasnikov A, Zhu H, Hixson P et al (2021) Structural analysis of the full-length human lrrk2. Cell 184(13):3519\u20133527","journal-title":"Cell"},{"issue":"5","key":"1084_CR27","doi-asserted-by":"publisher","first-page":"1579","DOI":"10.1073\/pnas.1817889116","volume":"116","author":"P Zhang","year":"2019","unstructured":"Zhang P, Fan Y, Ru H et al (2019) Crystal structure of the wd40 domain dimer of lrrk2. Proc Natl Acad Sci 116(5):1579\u20131584","journal-title":"Proc Natl Acad Sci"},{"issue":"1\u201379","key":"1084_CR28","first-page":"4","volume":"1","author":"G Landrum","year":"2013","unstructured":"Landrum G (2013) Rdkit documentation. Release 1(1\u201379):4","journal-title":"Release"},{"key":"1084_CR29","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s13321-015-0095-1","volume":"7","author":"S Kothiwale","year":"2015","unstructured":"Kothiwale S, Mendenhall JL, Meiler J (2015) Bcl: C onf: small molecule conformational sampling using a knowledge based rotamer library. J Cheminform 7:1\u201315","journal-title":"J Cheminform"},{"issue":"1","key":"1084_CR30","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1021\/acs.jcim.0c01140","volume":"61","author":"J Mendenhall","year":"2020","unstructured":"Mendenhall J, Brown BP, Kothiwale S et al (2020) Bcl: Conf: improved open-source knowledge-based conformation sampling using the crystallography open database. J Chem Inf Model 61(1):189\u2013201","journal-title":"J Chem Inf Model"},{"key":"1084_CR31","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1007\/978-1-61779-465-0_10","volume-title":"Computational drug discovery and design","author":"G Lemmon","year":"2012","unstructured":"Lemmon G, Meiler J (2012) Rosetta ligand docking with flexible xml protocols. In: Baron R (ed) Computational drug discovery and design. Springer, New York, pp 143\u2013155"},{"issue":"1","key":"1084_CR32","doi-asserted-by":"publisher","first-page":"528","DOI":"10.1021\/acs.jctc.9b00591","volume":"16","author":"C Tian","year":"2019","unstructured":"Tian C, Kasavajhala K, Belfon KA et al (2019) ff19sb: amino-acid-specific protein backbone parameters trained against quantum mechanics energy surfaces in solution. J Chem Theory Comput 16(1):528\u2013552","journal-title":"J Chem Theory Comput"},{"key":"1084_CR33","unstructured":"Ester M, Kriegel HP, Sander J, et\u00a0al (1996) A density-based algorithm for discovering clusters in large spatial databases with noise. In: kdd, pp 226\u2013231"},{"key":"1084_CR34","first-page":"545","volume-title":"Methods in Enzymology","author":"A Leaver-Fay","year":"2011","unstructured":"Leaver-Fay A, Tyka M, Lewis SM et al (2011) Rosetta3: an object-oriented software suite for the simulation and design of macromolecules. In: Johnson ML, Brand L (eds) Methods in enzymology. Elsevier, Amsterdam, pp 545\u2013574"},{"issue":"2","key":"1084_CR35","doi-asserted-by":"publisher","first-page":"607","DOI":"10.1016\/j.jmb.2010.11.008","volume":"405","author":"MD Tyka","year":"2011","unstructured":"Tyka MD, Keedy DA, Andr\u00e9 I et al (2011) Alternate states of proteins revealed by detailed energy landscape mapping. J Mol Biol 405(2):607\u2013618","journal-title":"J Mol Biol"},{"issue":"1\u20133","key":"1084_CR36","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/S0169-409X(96)00423-1","volume":"23","author":"CA Lipinski","year":"1997","unstructured":"Lipinski CA, Lombardo F, Dominy BW et al (1997) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 23(1\u20133):3\u201325","journal-title":"Adv Drug Deliv Rev"},{"issue":"22","key":"1084_CR37","doi-asserted-by":"publisher","first-page":"8521","DOI":"10.1021\/acs.jcim.4c01267","volume":"64","author":"F Li","year":"2024","unstructured":"Li F, Ackloo S, Arrowsmith CH et al (2024) Cache challenge #1: targeting the wdr domain of lrrk2, a Parkinson\u2019s disease associated protein. J Chem Inf Model 64(22):8521\u20138536","journal-title":"J Chem Inf Model"},{"issue":"7","key":"1084_CR38","doi-asserted-by":"publisher","first-page":"2719","DOI":"10.1021\/jm901137j","volume":"53","author":"JB Baell","year":"2010","unstructured":"Baell JB, Holloway GA (2010) New substructure filters for removal of pan assay interference compounds (pains) from screening libraries and for their exclusion in bioassays. J Med Chem 53(7):2719\u20132740","journal-title":"J Med Chem"},{"key":"1084_CR39","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/1758-2946-5-26","volume":"5","author":"S Riniker","year":"2013","unstructured":"Riniker S, Landrum GA (2013) Open-source platform to benchmark fingerprints for ligand-based virtual screening. J Cheminform 5:1\u201317","journal-title":"J Cheminform"},{"issue":"5","key":"1084_CR40","doi-asserted-by":"publisher","first-page":"742","DOI":"10.1021\/ci100050t","volume":"50","author":"D Rogers","year":"2010","unstructured":"Rogers D, Hahn M (2010) Extended-connectivity fingerprints. J Chem Inf Model 50(5):742\u2013754","journal-title":"J Chem Inf Model"},{"issue":"5","key":"1084_CR41","doi-asserted-by":"publisher","first-page":"2489","DOI":"10.1021\/acs.jmedchem.0c02227","volume":"64","author":"A Fischer","year":"2021","unstructured":"Fischer A, Smiesko M, Sellner M et al (2021) Decision making in structure-based drug discovery: visual inspection of docking results. J Med Chem 64(5):2489\u20132500","journal-title":"J Med Chem"},{"issue":"3","key":"1084_CR42","doi-asserted-by":"publisher","first-page":"1128","DOI":"10.1016\/j.ejmech.2008.06.013","volume":"44","author":"P Axerio-Cilies","year":"2009","unstructured":"Axerio-Cilies P, Casta\u00f1eda IP, Mirza A et al (2009) Investigation of the incidence of \u201cundesirable\u2019\u2019 molecular moieties for high-throughput screening compound libraries in marketed drug compounds. Eur J Med Chem 44(3):1128\u20131134","journal-title":"Eur J Med Chem"},{"issue":"10","key":"1084_CR43","doi-asserted-by":"publisher","first-page":"2066","DOI":"10.1016\/j.bmc.2019.04.002","volume":"27","author":"JS Martin","year":"2019","unstructured":"Martin JS, MacKenzie CJ, Fletcher D et al (2019) Characterising covalent warhead reactivity. Bioorg Med Chem 27(10):2066\u20132074","journal-title":"Bioorg Med Chem"},{"issue":"1","key":"1084_CR44","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1038\/s41589-021-00898-0","volume":"18","author":"D Dilworth","year":"2022","unstructured":"Dilworth D, Hanley RP, Ferreira de Freitas R et al (2022) A chemical probe targeting the pwwp domain alters nsd2 nucleolar localization. Nat Chem Biol 18(1):56\u201363","journal-title":"Nat Chem Biol"},{"issue":"5","key":"1084_CR45","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1016\/S0968-0004(99)01384-5","volume":"24","author":"TF Smith","year":"1999","unstructured":"Smith TF, Gaitatzes C, Saxena K et al (1999) The wd repeat: a common architecture for diverse functions. Trends Biochem Sci 24(5):181\u2013185","journal-title":"Trends Biochem Sci"},{"issue":"8","key":"1084_CR46","doi-asserted-by":"publisher","first-page":"571","DOI":"10.1038\/nchembio.1859","volume":"11","author":"F Grebien","year":"2015","unstructured":"Grebien F, Vedadi M, Getlik M et al (2015) Pharmacological targeting of the wdr5-mll interaction in c\/ebp$$\\alpha$$ n-terminal leukemia. Nat Chem Biol 11(8):571\u2013578","journal-title":"Nat Chem Biol"},{"issue":"13","key":"1084_CR47","doi-asserted-by":"publisher","first-page":"4070","DOI":"10.1021\/acs.jcim.3c00082","volume":"63","author":"SW Kimani","year":"2023","unstructured":"Kimani SW, Owen J, Green SR et al (2023) Discovery of a novel dcaf1 ligand using a drug-target interaction prediction model: generalizing machine learning to new drug targets. J Chem Inf Model 63(13):4070\u20134078","journal-title":"J Chem Inf Model"},{"issue":"8","key":"1084_CR48","doi-asserted-by":"publisher","first-page":"6287","DOI":"10.1021\/acs.jmedchem.2c00195","volume":"65","author":"KB Teuscher","year":"2022","unstructured":"Teuscher KB, Meyers KM, Wei Q et al (2022) Discovery of potent orally bioavailable wd repeat domain 5 (wdr5) inhibitors using a pharmacophore-based optimization. J Med Chem 65(8):6287\u20136312","journal-title":"J Med Chem"},{"issue":"11","key":"1084_CR49","doi-asserted-by":"publisher","first-page":"4085","DOI":"10.1073\/pnas.1319827111","volume":"111","author":"ES Feldblum","year":"2014","unstructured":"Feldblum ES, Arkin IT (2014) Strength of a bifurcated h bond. Proc Natl Acad Sci 111(11):4085\u20134090","journal-title":"Proc Natl Acad Sci"},{"issue":"1\u20132","key":"1084_CR50","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1016\/0014-5793(91)81032-4","volume":"288","author":"R Prei\u00dfner","year":"1991","unstructured":"Prei\u00dfner R, Egner U, Saenger W (1991) Occurrence of bifurcated three-center hydrogen bonds in protpins. FEBS Lett 288(1\u20132):192\u2013196","journal-title":"FEBS Lett"},{"issue":"48","key":"1084_CR51","doi-asserted-by":"publisher","first-page":"9925","DOI":"10.1021\/jp9824813","volume":"102","author":"I Rozas","year":"1998","unstructured":"Rozas I, Alkorta I, Elguero J (1998) Bifurcated hydrogen bonds: three-centered interactions. J Phys Chem A 102(48):9925\u20139932","journal-title":"J Phys Chem A"},{"issue":"1","key":"1084_CR52","doi-asserted-by":"publisher","first-page":"7526","DOI":"10.1038\/s41598-024-54655-z","volume":"14","author":"AM Sousa","year":"2024","unstructured":"Sousa AM, Moreira POL, Monte Neto RL et al (2024) Ai is a viable alternative to high throughput screening: a 318-target study. Sci Rep 14(1):7526","journal-title":"Sci Rep"},{"issue":"17","key":"1084_CR53","doi-asserted-by":"publisher","first-page":"6560","DOI":"10.1021\/jm301916b","volume":"56","author":"T Zhu","year":"2013","unstructured":"Zhu T, Cao S, Su PC et al (2013) Hit identification and optimization in virtual screening: practical recommendations based on a critical literature analysis: miniperspective. J Med Chem 56(17):6560\u20136572","journal-title":"J Med Chem"},{"issue":"13","key":"1084_CR54","doi-asserted-by":"publisher","first-page":"5344","DOI":"10.1021\/acs.jcim.4c00601","volume":"64","author":"M Eguida","year":"2024","unstructured":"Eguida M, Bret G, Sindt F et al (2024) Subpocket similarity-based hit identification for challenging targets: application to the wdr domain of lrrk2. J Chem Inf Model 64(13):5344\u20135355","journal-title":"J Chem Inf Model"},{"issue":"8","key":"1084_CR55","doi-asserted-by":"publisher","first-page":"3430","DOI":"10.1039\/D4SC07532C","volume":"16","author":"A Mettu","year":"2025","unstructured":"Mettu A, Glavatskikh M, Wang X et al (2025) Functionally active modulators targeting the lrrk2 wd40 repeat domain identified by frase-bot in cache challenge# 1. Chem Sci 16(8):3430\u20133439","journal-title":"Chem Sci"},{"issue":"24","key":"1084_CR56","doi-asserted-by":"publisher","first-page":"9388","DOI":"10.1021\/acs.jcim.4c01429","volume":"64","author":"I Dunn","year":"2024","unstructured":"Dunn I, Pirhadi S, Wang Y et al (2024) Cache challenge# 1: docking with gnina is all you need. J Chem Inf Model 64(24):9388\u20139396","journal-title":"J Chem Inf Model"},{"issue":"23","key":"1084_CR57","doi-asserted-by":"publisher","first-page":"8800","DOI":"10.1039\/D3SC06880C","volume":"15","author":"E Gutkin","year":"2024","unstructured":"Gutkin E, Gusev F, Gentile F et al (2024) In silico screening of lrrk2 wdr domain inhibitors using deep docking and free energy simulations. Chem Sci 15(23):8800\u20138812","journal-title":"Chem Sci"},{"key":"1084_CR58","doi-asserted-by":"crossref","unstructured":"Minibaeva G, Polishchuk P (2024) Crem-dock: de novo design of synthetically feasible compounds guided by molecular docking. ChemRxiv preprint. https:\/\/doi.org\/1026434\/chemrxiv-2024-fpzqb-v3","DOI":"10.26434\/chemrxiv-2024-fpzqb"},{"issue":"4","key":"1084_CR59","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1016\/S1093-3263(01)00125-5","volume":"20","author":"RD Clark","year":"2002","unstructured":"Clark RD, Strizhev A, Leonard JM et al (2002) Consensus scoring for ligand\/protein interactions. J Mol Graph Model 20(4):281\u2013295","journal-title":"J Mol Graph Model"},{"issue":"5","key":"1084_CR60","doi-asserted-by":"publisher","first-page":"1509","DOI":"10.1021\/ct900587b","volume":"6","author":"D Shivakumar","year":"2010","unstructured":"Shivakumar D, Williams J, Wu Y et al (2010) Prediction of absolute solvation free energies using molecular dynamics free energy perturbation and the opls force field. J Chem Theory Comput 6(5):1509\u20131519","journal-title":"J Chem Theory Comput"},{"issue":"11","key":"1084_CR61","doi-asserted-by":"publisher","first-page":"2111","DOI":"10.1016\/j.drudis.2019.06.020","volume":"24","author":"AJ Carter","year":"2019","unstructured":"Carter AJ, Kraemer O, Zwick M et al (2019) Target 2035: probing the human proteome. Drug Discov Today 24(11):2111\u20132115","journal-title":"Drug Discov Today"}],"container-title":["Journal of Cheminformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13321-025-01084-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13321-025-01084-3\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13321-025-01084-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,25]],"date-time":"2025-09-25T16:02:51Z","timestamp":1758816171000},"score":1,"resource":{"primary":{"URL":"https:\/\/jcheminf.biomedcentral.com\/articles\/10.1186\/s13321-025-01084-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,25]]},"references-count":61,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["1084"],"URL":"https:\/\/doi.org\/10.1186\/s13321-025-01084-3","relation":{"has-preprint":[{"id-type":"doi","id":"10.26434\/chemrxiv-2025-7v2ts","asserted-by":"object"}]},"ISSN":["1758-2946"],"issn-type":[{"value":"1758-2946","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,25]]},"assertion":[{"value":"19 April 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 August 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 September 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no Competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"145"}}