{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T22:13:55Z","timestamp":1769552035497,"version":"3.49.0"},"reference-count":53,"publisher":"Springer Science and Business Media LLC","issue":"9","license":[{"start":{"date-parts":[[2019,9,1]],"date-time":"2019-09-01T00:00:00Z","timestamp":1567296000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,9,21]],"date-time":"2019-09-21T00:00:00Z","timestamp":1569024000000},"content-version":"vor","delay-in-days":20,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100012550","name":"Nemzeti Kutat\u00e1si, Fejleszt\u00e9si \u00e9s Innovaci\u00f3s Alap","doi-asserted-by":"publisher","award":["2017-1.2.1-NKP-2017-00002"],"award-info":[{"award-number":["2017-1.2.1-NKP-2017-00002"]}],"id":[{"id":"10.13039\/501100012550","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Comput Aided Mol Des"],"published-print":{"date-parts":[[2019,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n              <jats:p>Stabilizing unique receptor conformations, allosteric modulators of G-protein coupled receptors (GPCRs) might open novel treatment options due to their new pharmacological action, their enhanced specificity and selectivity in both binding and signaling. Ligand binding occurs at intrahelical allosteric sites and involves significant induced fit effects that include conformational changes in the local protein environment and water networks. Based on the analysis of available crystal structures of metabotropic glutamate receptor 5 (mGlu<jats:sub>5<\/jats:sub>) we investigated these effects in the binding of mGlu<jats:sub>5<\/jats:sub> receptor negative allosteric modulators. A large set of retrospective virtual screens revealed that the use of multiple protein structures and the inclusion of selected water molecules improves virtual screening performance compared to conventional docking strategies. The role of water molecules and protein flexibility in ligand binding can be taken into account efficiently by the proposed docking protocol that provided reasonable enrichment of true positives. This protocol is expected to be useful also for identifying intrahelical allosteric modulators for other GPCR targets.<\/jats:p>","DOI":"10.1007\/s10822-019-00224-w","type":"journal-article","created":{"date-parts":[[2019,9,21]],"date-time":"2019-09-21T07:03:02Z","timestamp":1569049382000},"page":"787-797","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["The role of water and protein flexibility in the structure-based virtual screening of allosteric GPCR modulators: an mGlu5 receptor case study"],"prefix":"10.1007","volume":"33","author":[{"given":"Zolt\u00e1n","family":"Orgov\u00e1n","sequence":"first","affiliation":[]},{"given":"Gy\u00f6rgy G.","family":"Ferenczy","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1039-7809","authenticated-orcid":false,"given":"Gy\u00f6rgy M.","family":"Keser\u0171","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2019,9,21]]},"reference":[{"key":"224_CR1","doi-asserted-by":"publisher","first-page":"1923","DOI":"10.2174\/1568026614666140929124445","volume":"14","author":"E Lionta","year":"2014","unstructured":"Lionta E, Spyrou G, Vassilatis DK, Cournia Z (2014) Structure-based virtual screening for drug discovery: principles, applications and recent advances. Curr Top Med Chem 14:1923\u20131938. \n                    https:\/\/doi.org\/10.2174\/1568026614666140929124445","journal-title":"Curr Top Med Chem"},{"key":"224_CR2","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1016\/B978-0-12-407865-9.00015-7","volume":"522","author":"AJ Kooistra","year":"2013","unstructured":"Kooistra AJ, Roumen L, Leurs R et al (2013) From heptahelical bundle to hits from the haystack: structure-based virtual screening for GPCR ligands. Methods Enzymol 522:279\u2013336. \n                    https:\/\/doi.org\/10.1016\/B978-0-12-407865-9.00015-7","journal-title":"Methods Enzymol"},{"key":"224_CR3","doi-asserted-by":"publisher","DOI":"10.3390\/molecules22071188","author":"D Bartuzi","year":"2017","unstructured":"Bartuzi D, Kaczor AA, Matosiuk D (2017) Signaling within allosteric machines: signal transmission pathways inside G protein-coupled receptors. Molecules. \n                    https:\/\/doi.org\/10.3390\/molecules22071188","journal-title":"Molecules"},{"key":"224_CR4","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1038\/s41586-018-0259-z","volume":"559","author":"DM Thal","year":"2018","unstructured":"Thal DM, Glukhova A, Sexton PM, Christopoulos A (2018) Structural insights into G-protein-coupled receptor allostery. Nature 559:45\u201353. \n                    https:\/\/doi.org\/10.1038\/s41586-018-0259-z","journal-title":"Nature"},{"key":"224_CR5","doi-asserted-by":"publisher","first-page":"829","DOI":"10.1038\/nrd.2017.178","volume":"16","author":"AS Hauser","year":"2017","unstructured":"Hauser AS, Attwood MM, Rask-Andersen M et al (2017) Trends in GPCR drug discovery: new agents, targets and indications. Nat Rev Drug Discov 16:829\u2013842. \n                    https:\/\/doi.org\/10.1038\/nrd.2017.178","journal-title":"Nat Rev Drug Discov"},{"key":"224_CR6","doi-asserted-by":"publisher","first-page":"6180","DOI":"10.1038\/s41598-019-42618-8","volume":"9","author":"AE Wakefield","year":"2019","unstructured":"Wakefield AE, Mason JS, Vajda S, Keser\u0171 GM (2019) Analysis of tractable allosteric sites in G protein-coupled receptors. Sci Rep 9:6180. \n                    https:\/\/doi.org\/10.1038\/s41598-019-42618-8","journal-title":"Sci Rep"},{"key":"224_CR7","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1038\/nature13396","volume":"511","author":"AS Dor\u00e9","year":"2014","unstructured":"Dor\u00e9 AS, Okrasa K, Patel JC et al (2014) Structure of class C GPCR metabotropic glutamate receptor 5 transmembrane domain. Nature 511:557\u2013562. \n                    https:\/\/doi.org\/10.1038\/nature13396","journal-title":"Nature"},{"key":"224_CR8","doi-asserted-by":"publisher","first-page":"6653","DOI":"10.1021\/acs.jmedchem.5b00892","volume":"58","author":"JA Christopher","year":"2015","unstructured":"Christopher JA, Aves SJ, Bennett KA et al (2015) Fragment and structure-based drug discovery for a class C GPCR: discovery of the mGlu5 negative allosteric modulator HTL14242 (3-Chloro-5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]benzonitrile). J Med Chem 58:6653\u20136664. \n                    https:\/\/doi.org\/10.1021\/acs.jmedchem.5b00892","journal-title":"J Med Chem"},{"key":"224_CR9","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.7b01722","author":"JA Christopher","year":"2018","unstructured":"Christopher JA, Orgov\u00e1n Z, Congreve M et al (2018) Structure-based optimization strategies for G protein-coupled receptor (GPCR) allosteric modulators: a case study from analyses of new metabotropic glutamate receptor 5 (mGlu 5) X-ray structures. J Med Chem. \n                    https:\/\/doi.org\/10.1021\/acs.jmedchem.7b01722","journal-title":"J Med Chem"},{"key":"224_CR10","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1038\/s41586-019-0881-4","volume":"566","author":"A Koehl","year":"2019","unstructured":"Koehl A, Hu H, Feng D et al (2019) Structural insights into the activation of metabotropic glutamate receptors. Nature 566:79\u201384. \n                    https:\/\/doi.org\/10.1038\/s41586-019-0881-4","journal-title":"Nature"},{"key":"224_CR11","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1016\/S0959-4388(00)00219-1","volume":"11","author":"S Alagarsamy","year":"2001","unstructured":"Alagarsamy S, Sorensen SD, Conn PJ (2001) Coordinate regulation of metabotropic glutamate receptors. Curr Opin Neurobiol 11:357\u2013362","journal-title":"Curr Opin Neurobiol"},{"key":"224_CR12","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1146\/annurev.pharmtox.011008.145533","volume":"50","author":"CM Niswender","year":"2010","unstructured":"Niswender CM, Conn PJ (2010) Metabotropic glutamate receptors: physiology, pharmacology, and disease. Annu Rev Pharmacol Toxicol 50:295\u2013322. \n                    https:\/\/doi.org\/10.1146\/annurev.pharmtox.011008.145533","journal-title":"Annu Rev Pharmacol Toxicol"},{"key":"224_CR13","doi-asserted-by":"publisher","first-page":"837","DOI":"10.1016\/j.tips.2017.05.010","volume":"38","author":"M Congreve","year":"2017","unstructured":"Congreve M, Oswald C, Marshall FH (2017) Applying structure-based drug design approaches to allosteric modulators of GPCRs. Trends Pharmacol Sci 38:837\u2013847. \n                    https:\/\/doi.org\/10.1016\/j.tips.2017.05.010","journal-title":"Trends Pharmacol Sci"},{"key":"224_CR14","doi-asserted-by":"publisher","first-page":"6707","DOI":"10.1021\/acs.chemrev.5b00656","volume":"116","author":"CW Lindsley","year":"2016","unstructured":"Lindsley CW, Emmitte KA, Hopkins CR et al (2016) Practical strategies and concepts in GPCR allosteric modulator discovery: recent advances with metabotropic glutamate receptors. Chem Rev 116:6707\u20136741. \n                    https:\/\/doi.org\/10.1021\/acs.chemrev.5b00656","journal-title":"Chem Rev"},{"key":"224_CR15","doi-asserted-by":"publisher","first-page":"2456","DOI":"10.1021\/acs.jcim.8b00924","volume":"59","author":"C Llinas del Torrent","year":"2019","unstructured":"Llinas del Torrent C, Casajuana-Martin N, Pardo L et al (2019) Mechanisms underlying allosteric molecular switches of metabotropic glutamate receptor 5. J Chem Inf Model 59:2456\u20132466. \n                    https:\/\/doi.org\/10.1021\/acs.jcim.8b00924","journal-title":"J Chem Inf Model"},{"key":"224_CR16","doi-asserted-by":"publisher","first-page":"5790","DOI":"10.1016\/j.bmc.2014.09.033","volume":"22","author":"I Vranesic","year":"2014","unstructured":"Vranesic I, Ofner S, Flor PJ et al (2014) AFQ056\/mavoglurant, a novel clinically effective mGluR5 antagonist: identification, SAR and pharmacological characterization. Bioorg Med Chem 22:5790\u20135803. \n                    https:\/\/doi.org\/10.1016\/j.bmc.2014.09.033","journal-title":"Bioorg Med Chem"},{"key":"224_CR17","doi-asserted-by":"publisher","first-page":"1493","DOI":"10.1016\/S0028-3908(99)00082-9","volume":"38","author":"F Gasparini","year":"1999","unstructured":"Gasparini F, Lingenh\u00f6hl K, Stoehr N et al (1999) 2-Methyl-6-(phenylethynyl)-pyridine (MPEP), a potent, selective and systemically active mGlu5 receptor antagonist. Neuropharmacology 38:1493\u20131503. \n                    https:\/\/doi.org\/10.1016\/S0028-3908(99)00082-9","journal-title":"Neuropharmacology"},{"key":"224_CR18","doi-asserted-by":"publisher","first-page":"1142","DOI":"10.1016\/j.bmcl.2005.11.092","volume":"16","author":"A W\u00e5llberg","year":"2006","unstructured":"W\u00e5llberg A, Nilsson K, \u00d6sterlund K et al (2006) Phenyl ureas of creatinine as mGluR5 antagonists. A structure\u2013activity relationship study of fenobam analogues. Bioorg Med Chem Lett 16:1142\u20131145. \n                    https:\/\/doi.org\/10.1016\/j.bmcl.2005.11.092","journal-title":"Bioorg Med Chem Lett"},{"key":"224_CR19","doi-asserted-by":"publisher","first-page":"33750","DOI":"10.1074\/jbc.M006230200","volume":"275","author":"A Pagano","year":"2000","unstructured":"Pagano A, Ruegg D, Litschig S et al (2000) The non-competitive antagonists 2-methyl-6-(phenylethynyl)pyridine and 7-hydroxyiminocyclopropan[b]chromen-1a-carboxylic acid ethyl ester interact with overlapping binding pockets in the transmembrane region of group I metabotropic glutamate receptors. J Biol Chem 275:33750\u201333758. \n                    https:\/\/doi.org\/10.1074\/jbc.M006230200","journal-title":"J Biol Chem"},{"key":"224_CR20","doi-asserted-by":"publisher","first-page":"440","DOI":"10.1002\/cmdc.201100578","volume":"7","author":"BH Kaae","year":"2012","unstructured":"Kaae BH, Harps\u00f8e K, Kvist T et al (2012) Structure\u2013activity relationships for negative allosteric mGluR5 modulators. ChemMedChem 7:440\u2013451. \n                    https:\/\/doi.org\/10.1002\/cmdc.201100578","journal-title":"ChemMedChem"},{"key":"224_CR21","doi-asserted-by":"publisher","first-page":"1476","DOI":"10.1021\/ci500127c","volume":"54","author":"JAR Dalton","year":"2014","unstructured":"Dalton JAR, G\u00f3mez-Santacana X, Llebaria A, Giraldo J (2014) Computational analysis of negative and positive allosteric modulator binding and function in metabotropic glutamate receptor 5 (in)activation. J Chem Inf Model 54:1476\u20131487. \n                    https:\/\/doi.org\/10.1021\/ci500127c","journal-title":"J Chem Inf Model"},{"key":"224_CR22","doi-asserted-by":"publisher","first-page":"3040","DOI":"10.1016\/j.bmc.2015.05.008","volume":"23","author":"A Anighoro","year":"2015","unstructured":"Anighoro A, Graziani D, Bettinelli I et al (2015) Insights into the interaction of negative allosteric modulators with the metabotropic glutamate receptor 5: discovery and computational modeling of a new series of ligands with nanomolar affinity. Bioorg Med Chem 23:3040\u20133058. \n                    https:\/\/doi.org\/10.1016\/j.bmc.2015.05.008","journal-title":"Bioorg Med Chem"},{"key":"224_CR23","doi-asserted-by":"publisher","first-page":"13869","DOI":"10.1038\/srep13869","volume":"5","author":"K Harps\u00f8e","year":"2015","unstructured":"Harps\u00f8e K, Isberg V, Tehan BG et al (2015) Selective negative allosteric modulation of metabotropic glutamate receptors\u2014a structural perspective of ligands and mutants. Sci Rep 5:13869. \n                    https:\/\/doi.org\/10.1038\/srep13869","journal-title":"Sci Rep"},{"key":"224_CR24","doi-asserted-by":"publisher","first-page":"414","DOI":"10.1016\/J.COMPBIOLCHEM.2018.12.016","volume":"78","author":"S Vijaya Prabhu","year":"2019","unstructured":"Vijaya Prabhu S, Singh SK (2019) E-pharmacophore-based screening of mGluR5 negative allosteric modulators for central nervous system disorder. Comput Biol Chem 78:414\u2013423. \n                    https:\/\/doi.org\/10.1016\/J.COMPBIOLCHEM.2018.12.016","journal-title":"Comput Biol Chem"},{"key":"224_CR25","doi-asserted-by":"publisher","DOI":"10.3390\/molecules24061098","author":"C Llinas Del Torrent","year":"2019","unstructured":"Llinas Del Torrent C, P\u00e9rez-Benito L, Tresadern G (2019) Computational drug design applied to the study of metabotropic glutamate receptors. Molecules. \n                    https:\/\/doi.org\/10.3390\/molecules24061098","journal-title":"Molecules"},{"key":"224_CR26","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1021\/ci200412p","volume":"52","author":"EA Gatica","year":"2012","unstructured":"Gatica EA, Cavasotto CN (2012) Ligand and decoy sets for docking to G protein-coupled receptors. J Chem Inf Model 52:1\u20136. \n                    https:\/\/doi.org\/10.1021\/ci200412p","journal-title":"J Chem Inf Model"},{"key":"224_CR27","doi-asserted-by":"publisher","first-page":"3284","DOI":"10.1021\/jm801533x","volume":"52","author":"AA Ivanov","year":"2009","unstructured":"Ivanov AA, Barak D, Jacobson KA (2009) Evaluation of homology modeling of G-protein-coupled receptors in light of the A2A adenosine receptor crystallographic structure. J Med Chem 52:3284\u20133292. \n                    https:\/\/doi.org\/10.1021\/jm801533x","journal-title":"J Med Chem"},{"key":"224_CR28","doi-asserted-by":"publisher","first-page":"1737","DOI":"10.1021\/ci5000455","volume":"54","author":"EB Lenselink","year":"2014","unstructured":"Lenselink EB, Beuming T, Sherman W et al (2014) Selecting an optimal number of binding site waters to improve virtual screening enrichments against the adenosine A2A receptor. J Chem Inf Model 54:1737\u20131746. \n                    https:\/\/doi.org\/10.1021\/ci5000455","journal-title":"J Chem Inf Model"},{"key":"224_CR29","doi-asserted-by":"publisher","DOI":"10.1080\/07391102.2019.1638302","author":"B J\u00f3j\u00e1rt","year":"2019","unstructured":"J\u00f3j\u00e1rt B, Orgov\u00e1n Z, M\u00e1rki \u00c1 et al (2019) Allosteric activation of metabotropic glutamate RECEPTOR 5. J Biomol Struct Dyn. \n                    https:\/\/doi.org\/10.1080\/07391102.2019.1638302","journal-title":"J Biomol Struct Dyn"},{"key":"224_CR30","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jcim.9b00045","author":"X Cong","year":"2019","unstructured":"Cong X, Ch\u00e9ron J-B, Golebiowski J et al (2019) Allosteric modulation mechanism of the mGluR5 transmembrane domain. J Chem Inf Model. \n                    https:\/\/doi.org\/10.1021\/acs.jcim.9b00045","journal-title":"J Chem Inf Model"},{"key":"224_CR31","doi-asserted-by":"publisher","DOI":"10.1021\/JM0608356","author":"N Huang","year":"2006","unstructured":"Huang N, Shoichet KB, Irwin JJ (2006) Benchmarking sets for molecular docking. J Med Chem. \n                    https:\/\/doi.org\/10.1021\/JM0608356","journal-title":"J Med Chem"},{"key":"224_CR32","doi-asserted-by":"publisher","first-page":"6582","DOI":"10.1021\/jm300687e","volume":"55","author":"MM Mysinger","year":"2012","unstructured":"Mysinger MM, Carchia M, Irwin JJ, Shoichet BK (2012) Directory of useful decoys, enhanced (DUD-E): better ligands and decoys for better benchmarking. J Med Chem 55:6582\u20136594. \n                    https:\/\/doi.org\/10.1021\/jm300687e","journal-title":"J Med Chem"},{"key":"224_CR33","doi-asserted-by":"publisher","first-page":"737","DOI":"10.1208\/s12248-015-9742-8","volume":"17","author":"Z Feng","year":"2015","unstructured":"Feng Z, Ma S, Hu G, Xie X-Q (2015) Allosteric binding site and activation mechanism of class C G-protein coupled receptors: metabotropic glutamate receptor family. AAPS J 17:737\u2013753. \n                    https:\/\/doi.org\/10.1208\/s12248-015-9742-8","journal-title":"AAPS J"},{"key":"224_CR34","doi-asserted-by":"publisher","first-page":"1862","DOI":"10.1007\/s11064-014-1248-8","volume":"39","author":"C M\u00f8lck","year":"2014","unstructured":"M\u00f8lck C, Harps\u00f8e K, Gloriam DE et al (2014) mGluR5: exploration of orthosteric and allosteric ligand binding pockets and their applications to drug discovery. Neurochem Res 39:1862\u20131875","journal-title":"Neurochem Res"},{"key":"224_CR35","doi-asserted-by":"publisher","first-page":"929","DOI":"10.1124\/mol.112.078808","volume":"82","author":"C Molck","year":"2012","unstructured":"Molck C, Harpsoe K, Gloriam DE et al (2012) Pharmacological characterization and modeling of the binding sites of novel 1,3-bis(pyridinylethynyl)benzenes as metabotropic glutamate receptor 5-selective negative allosteric modulators. Mol Pharmacol 82:929\u2013937. \n                    https:\/\/doi.org\/10.1124\/mol.112.078808","journal-title":"Mol Pharmacol"},{"key":"224_CR36","doi-asserted-by":"publisher","first-page":"D945","DOI":"10.1093\/nar\/gkw1074","volume":"45","author":"A Gaulton","year":"2017","unstructured":"Gaulton A, Hersey A, Nowotka M et al (2017) The ChEMBL database in 2017. Nucleic Acids Res 45:D945\u2013D954. \n                    https:\/\/doi.org\/10.1093\/nar\/gkw1074","journal-title":"Nucleic Acids Res"},{"key":"224_CR37","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1016\/J.JMGM.2010.05.008","volume":"29","author":"J Duan","year":"2010","unstructured":"Duan J, Dixon SL, Lowrie JF, Sherman W (2010) Analysis and comparison of 2D fingerprints: insights into database screening performance using eight fingerprint methods. J Mol Graph Model 29:157\u2013170. \n                    https:\/\/doi.org\/10.1016\/J.JMGM.2010.05.008","journal-title":"J Mol Graph Model"},{"key":"224_CR38","doi-asserted-by":"publisher","first-page":"771","DOI":"10.1021\/ci100062n","volume":"50","author":"M Sastry","year":"2010","unstructured":"Sastry M, Lowrie JF, Dixon SL, Sherman W (2010) Large-scale systematic analysis of 2D fingerprint methods and parameters to improve virtual screening enrichments. J Chem Inf Model 50:771\u2013784. \n                    https:\/\/doi.org\/10.1021\/ci100062n","journal-title":"J Chem Inf Model"},{"key":"224_CR39","unstructured":"Schr\u00f6dinger Suite 2018-1 (2016) Protein preparation wizard. Epik, Schr\u00f6dinger, LLC, New York"},{"key":"224_CR40","unstructured":"Maestro (2018) Schr\u00f6dinger, LLC, New York, NY"},{"key":"224_CR41","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1007\/s10822-013-9644-8","volume":"27","author":"GM Sastry","year":"2013","unstructured":"Sastry GM, Adzhigirey M, Day T et al (2013) Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments. J Comput Aided Mol Des 27:221\u2013234. \n                    https:\/\/doi.org\/10.1007\/s10822-013-9644-8","journal-title":"J Comput Aided Mol Des"},{"key":"224_CR42","doi-asserted-by":"publisher","first-page":"849","DOI":"10.1021\/jm00145a002","volume":"28","author":"PJ Goodford","year":"1985","unstructured":"Goodford PJ (1985) A computational procedure for determining energetically favorable binding sites on biologically important macromolecules. J Med Chem 28:849\u2013857. \n                    https:\/\/doi.org\/10.1021\/jm00145a002","journal-title":"J Med Chem"},{"key":"224_CR43","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1021\/ci9003317","volume":"50","author":"S Sciabola","year":"2010","unstructured":"Sciabola S, Stanton RV, Mills JE et al (2010) High-throughput virtual screening of proteins using GRID molecular interaction fields. J Chem Inf Model 50:155\u2013169. \n                    https:\/\/doi.org\/10.1021\/ci9003317","journal-title":"J Chem Inf Model"},{"key":"224_CR44","unstructured":"Glide (2017) Schr\u00f6dinger, LLC, New York"},{"key":"224_CR45","first-page":"319","volume-title":"KNIME: the Konstanz information miner","author":"MR Berthold","year":"2008","unstructured":"Berthold MR, Cebron N, Dill F et al (2008) KNIME: the Konstanz information miner. Springer, Berlin, pp 319\u2013326"},{"key":"224_CR46","doi-asserted-by":"publisher","first-page":"887","DOI":"10.1007\/s10822-014-9753-z","volume":"28","author":"A Nicholls","year":"2014","unstructured":"Nicholls A (2014) Confidence limits, error bars and method comparison in molecular modeling. Part 1: the calculation of confidence intervals. J Comput Aided Mol Des 28:887\u2013918. \n                    https:\/\/doi.org\/10.1007\/s10822-014-9753-z","journal-title":"J Comput Aided Mol Des"},{"key":"224_CR47","doi-asserted-by":"publisher","first-page":"1090","DOI":"10.2174\/092986712799320556","volume":"19","author":"B Trzaskowski","year":"2012","unstructured":"Trzaskowski B, Latek D, Yuan S et al (2012) Action of molecular switches in GPCRs\u2013theoretical and experimental studies. Curr Med Chem 19:1090\u20131109. \n                    https:\/\/doi.org\/10.2174\/092986712799320556","journal-title":"Curr Med Chem"},{"key":"224_CR48","doi-asserted-by":"publisher","first-page":"494","DOI":"10.1016\/j.tips.2009.06.003","volume":"30","author":"S Ahuja","year":"2009","unstructured":"Ahuja S, Smith SO (2009) Multiple switches in G protein-coupled receptor activation. Trends Pharmacol Sci 30:494\u2013502. \n                    https:\/\/doi.org\/10.1016\/j.tips.2009.06.003","journal-title":"Trends Pharmacol Sci"},{"key":"224_CR49","doi-asserted-by":"publisher","first-page":"1038","DOI":"10.3390\/molecules23051038","volume":"23","author":"D Ram\u00edrez","year":"2018","unstructured":"Ram\u00edrez D, Caballero J (2018) Is it reliable to take the molecular docking top scoring position as the best solution without considering available structural data? Molecules 23:1038. \n                    https:\/\/doi.org\/10.3390\/molecules23051038","journal-title":"Molecules"},{"key":"224_CR50","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1021\/jm030209y","volume":"47","author":"JA Erickson","year":"2004","unstructured":"Erickson JA, Jalaie M, Robertson DH et al (2004) Lessons in molecular recognition: the effects of ligand and protein flexibility on molecular docking accuracy. J Med Chem 47:45\u201355. \n                    https:\/\/doi.org\/10.1021\/jm030209y","journal-title":"J Med Chem"},{"key":"224_CR51","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1016\/J.JMB.2004.01.003","volume":"337","author":"CN Cavasotto","year":"2004","unstructured":"Cavasotto CN, Abagyan RA (2004) Protein flexibility in ligand docking and virtual screening to protein kinases. J Mol Biol 337:209\u2013225. \n                    https:\/\/doi.org\/10.1016\/J.JMB.2004.01.003","journal-title":"J Mol Biol"},{"key":"224_CR52","doi-asserted-by":"publisher","first-page":"651","DOI":"10.1007\/s10822-016-9946-8","volume":"30","author":"S Gathiaka","year":"2016","unstructured":"Gathiaka S, Liu S, Chiu M et al (2016) D3R grand challenge 2015: evaluation of protein\u2013ligand pose and affinity predictions. J Comput Aided Mol Des 30:651\u2013668. \n                    https:\/\/doi.org\/10.1007\/s10822-016-9946-8","journal-title":"J Comput Aided Mol Des"},{"key":"224_CR53","doi-asserted-by":"publisher","first-page":"5128","DOI":"10.3390\/ijms15035128","volume":"15","author":"M Bajda","year":"2014","unstructured":"Bajda M, Jo\u0144czyk J, Malawska B, Filipek S (2014) Application of computational methods for the design of BACE-1 inhibitors: validation of in silico modelling. Int J Mol Sci 15:5128\u20135139. \n                    https:\/\/doi.org\/10.3390\/ijms15035128","journal-title":"Int J Mol Sci"}],"container-title":["Journal of Computer-Aided Molecular Design"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s10822-019-00224-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1007\/s10822-019-00224-w\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s10822-019-00224-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,9,19]],"date-time":"2020-09-19T23:10:57Z","timestamp":1600557057000},"score":1,"resource":{"primary":{"URL":"http:\/\/link.springer.com\/10.1007\/s10822-019-00224-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,9]]},"references-count":53,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2019,9]]}},"alternative-id":["224"],"URL":"https:\/\/doi.org\/10.1007\/s10822-019-00224-w","relation":{},"ISSN":["0920-654X","1573-4951"],"issn-type":[{"value":"0920-654X","type":"print"},{"value":"1573-4951","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,9]]},"assertion":[{"value":"24 May 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 September 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 September 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}]}}