{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T18:21:55Z","timestamp":1776795715896,"version":"3.51.2"},"reference-count":78,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,4,2]],"date-time":"2019-04-02T00:00:00Z","timestamp":1554163200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004359","name":"Vetenskapsr\u00e5det","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Cheminform"],"published-print":{"date-parts":[[2019,12]]},"DOI":"10.1186\/s13321-019-0348-5","type":"journal-article","created":{"date-parts":[[2019,4,2]],"date-time":"2019-04-02T09:04:45Z","timestamp":1554195885000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":72,"title":["QligFEP: an automated workflow for small molecule free energy calculations in Q"],"prefix":"10.1186","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4951-9220","authenticated-orcid":false,"given":"Willem","family":"Jespers","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1775-586X","authenticated-orcid":false,"given":"Mauricio","family":"Esguerra","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2091-0610","authenticated-orcid":false,"given":"Johan","family":"\u00c5qvist","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0459-3491","authenticated-orcid":false,"given":"Hugo","family":"Guti\u00e9rrez-de-Ter\u00e1n","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2019,4,2]]},"reference":[{"key":"348_CR1","doi-asserted-by":"publisher","first-page":"1157","DOI":"10.1002\/jcc.20035","volume":"25","author":"J Wang","year":"2004","unstructured":"Wang J, Wolf RM, Caldwell JW et al (2004) Development and testing of a general Amber force field. J Comput Chem 25:1157\u20131174. \n                    https:\/\/doi.org\/10.1002\/jcc.20035","journal-title":"J Comput Chem"},{"key":"348_CR2","doi-asserted-by":"publisher","first-page":"712","DOI":"10.1002\/prot.21123","volume":"65","author":"V Hornak","year":"2006","unstructured":"Hornak V, Abel R, Okur A et al (2006) Comparison of multiple amber force fields and development of improved protein backbone parameters. Proteins Struct Funct Genet 65:712\u2013725","journal-title":"Proteins Struct Funct Genet"},{"key":"348_CR3","doi-asserted-by":"publisher","first-page":"2135","DOI":"10.1002\/jcc.23354","volume":"34","author":"J Huang","year":"2013","unstructured":"Huang J, Mackerell AD (2013) CHARMM36 all-atom additive protein force field: validation based on comparison to NMR data. J Comput Chem 34:2135\u20132145. \n                    https:\/\/doi.org\/10.1002\/jcc.23354","journal-title":"J Comput Chem"},{"key":"348_CR4","doi-asserted-by":"publisher","first-page":"3499","DOI":"10.1021\/acs.jctc.5b00356","volume":"11","author":"MJ Robertson","year":"2015","unstructured":"Robertson MJ, Tirado-Rives J, Jorgensen WL (2015) Improved peptide and protein torsional energetics with the OPLS-AA force field. J Chem Theory Comput 11:3499\u20133509. \n                    https:\/\/doi.org\/10.1021\/acs.jctc.5b00356","journal-title":"J Chem Theory Comput"},{"key":"348_CR5","doi-asserted-by":"publisher","first-page":"W331","DOI":"10.1093\/nar\/gkx312","volume":"45","author":"LS Dodda","year":"2017","unstructured":"Dodda LS, De Vaca IC, Tirado-Rives J, Jorgensen WL (2017) LigParGen web server: an automatic OPLS-AA parameter generator for organic ligands. Nucleic Acids Res 45:W331\u2013W336. \n                    https:\/\/doi.org\/10.1093\/nar\/gkx312","journal-title":"Nucleic Acids Res"},{"key":"348_CR6","doi-asserted-by":"publisher","first-page":"611","DOI":"10.1016\/j.bpj.2010.12.3708","volume":"100","author":"Lee K Il","year":"2011","unstructured":"Il Lee K, Rui H, Pastor RW, Im W (2011) Brownian dynamics simulations of ion transport through the VDAC. Biophys J 100:611\u2013619. \n                    https:\/\/doi.org\/10.1016\/j.bpj.2010.12.3708","journal-title":"Biophys J"},{"key":"348_CR7","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1016\/0097-8485(84)85020-2","volume":"8","author":"BL Tembre","year":"1984","unstructured":"Tembre BL, Mc Cammon JA (1984) Ligand-receptor interactions. Comput Chem 8:281\u2013283. \n                    https:\/\/doi.org\/10.1016\/0097-8485(84)85020-2","journal-title":"Comput Chem"},{"key":"348_CR8","doi-asserted-by":"publisher","first-page":"2911","DOI":"10.1021\/acs.jcim.7b00564","volume":"57","author":"Z Cournia","year":"2017","unstructured":"Cournia Z, Allen B, Sherman W (2017) Relative binding free energy calculations in drug discovery: recent advances and practical considerations. J Chem Inf Model 57:2911\u20132937","journal-title":"J Chem Inf Model"},{"key":"348_CR9","doi-asserted-by":"publisher","first-page":"2485","DOI":"10.1021\/acs.jcim.5b00368","volume":"55","author":"HH Loeffler","year":"2015","unstructured":"Loeffler HH, Michel J, Woods C (2015) FESetup: automating setup for alchemical free energy simulations. J Chem Inf Model 55:2485\u20132490. \n                    https:\/\/doi.org\/10.1021\/acs.jcim.5b00368","journal-title":"J Chem Inf Model"},{"key":"348_CR10","doi-asserted-by":"publisher","first-page":"755","DOI":"10.1007\/s10822-013-9678-y","volume":"27","author":"S Liu","year":"2013","unstructured":"Liu S, Wu Y, Lin T et al (2013) Lead optimization mapper: automating free energy calculations for lead optimization. J Comput Aided Mol Des 27:755\u2013770. \n                    https:\/\/doi.org\/10.1007\/s10822-013-9678-y","journal-title":"J Comput Aided Mol Des"},{"key":"348_CR11","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1063\/1.881812","volume":"50","author":"D Frenkel","year":"2008","unstructured":"Frenkel D, Smit B, Ratner MA (2008) Understanding molecular simulation: from algorithms to applications. Phys Today 50:66. \n                    https:\/\/doi.org\/10.1063\/1.881812","journal-title":"Phys Today"},{"key":"348_CR12","doi-asserted-by":"publisher","first-page":"e1003585","DOI":"10.1371\/journal.pcbi.1003585","volume":"10","author":"L Boukharta","year":"2014","unstructured":"Boukharta L, Guti\u00e9rrez-de-Ter\u00e1n H, \u00c5qvist J (2014) Computational prediction of alanine scanning and ligand binding energetics in G-protein coupled receptors. PLoS Comput Biol 10:e1003585. \n                    https:\/\/doi.org\/10.1371\/journal.pcbi.1003585","journal-title":"PLoS Comput Biol"},{"key":"348_CR13","doi-asserted-by":"publisher","first-page":"3522","DOI":"10.1039\/C4CC09517K","volume":"51","author":"H Ker\u00e4nen","year":"2015","unstructured":"Ker\u00e4nen H, \u00c5qvist J, Guti\u00e9rrez-de-Ter\u00e1n H (2015) Free energy calculations of A 2A adenosine receptor mutation effects on agonist binding. Chem Commun 51:3522\u20133525. \n                    https:\/\/doi.org\/10.1039\/C4CC09517K","journal-title":"Chem Commun"},{"key":"348_CR14","doi-asserted-by":"publisher","first-page":"348","DOI":"10.1002\/jcc.23804","volume":"36","author":"V Gapsys","year":"2015","unstructured":"Gapsys V, Michielssens S, Seeliger D, de Groot BL (2015) pmx: automated protein structure and topology generation for alchemical perturbations. J Comput Chem 36:348\u2013354. \n                    https:\/\/doi.org\/10.1002\/jcc.23804","journal-title":"J Comput Chem"},{"key":"348_CR15","doi-asserted-by":"publisher","first-page":"675","DOI":"10.1007\/s10822-013-9672-4","volume":"27","author":"PG Polishchuk","year":"2013","unstructured":"Polishchuk PG, Madzhidov TI, Varnek A (2013) Estimation of the size of drug-like chemical space based on GDB-17 data. J Comput Aided Mol Des 27:675\u2013679. \n                    https:\/\/doi.org\/10.1007\/s10822-013-9672-4","journal-title":"J Comput Aided Mol Des"},{"key":"348_CR16","doi-asserted-by":"publisher","first-page":"722","DOI":"10.1021\/ar500432k","volume":"48","author":"JL Reymond","year":"2015","unstructured":"Reymond JL (2015) The chemical space project. Acc Chem Res 48:722\u2013730. \n                    https:\/\/doi.org\/10.1021\/ar500432k","journal-title":"Acc Chem Res"},{"key":"348_CR17","doi-asserted-by":"publisher","first-page":"2695","DOI":"10.1021\/ja512751q","volume":"137","author":"L Wang","year":"2015","unstructured":"Wang L, Wu Y, Deng Y et al (2015) Accurate and reliable prediction of relative ligand binding potency in prospective drug discovery by way of a modern free-energy calculation protocol and force field. J Am Chem Soc 137:2695\u20132703. \n                    https:\/\/doi.org\/10.1021\/ja512751q","journal-title":"J Am Chem Soc"},{"key":"348_CR18","doi-asserted-by":"publisher","first-page":"965","DOI":"10.1002\/jcc.23218","volume":"34","author":"N Homeyer","year":"2013","unstructured":"Homeyer N, Gohlke H (2013) FEW: a workflow tool for free energy calculations of ligand binding. J Comput Chem 34:965\u2013973. \n                    https:\/\/doi.org\/10.1002\/jcc.23218","journal-title":"J Comput Chem"},{"key":"348_CR19","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1021\/ci4004199","volume":"54","author":"CD Christ","year":"2014","unstructured":"Christ CD, Fox T (2014) Accuracy assessment and automation of free energy calculations for drug design. J Chem Inf Model 54:108\u2013120. \n                    https:\/\/doi.org\/10.1021\/ci4004199","journal-title":"J Chem Inf Model"},{"key":"348_CR20","doi-asserted-by":"publisher","first-page":"639","DOI":"10.1007\/s10822-010-9363-3","volume":"24","author":"J Michel","year":"2010","unstructured":"Michel J, Essex JW (2010) Prediction of protein-ligand binding affinity by free energy simulations: assumptions, pitfalls and expectations. J Comput Aided Mol Des 24:639\u2013658","journal-title":"J Comput Aided Mol Des"},{"key":"348_CR21","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1021\/acs.jcim.5b00057","volume":"55","author":"S Liu","year":"2015","unstructured":"Liu S, Wang L, Mobley DL (2015) Is ring breaking feasible in relative binding free energy calculations? J Chem Inf Model 55:727\u2013735. \n                    https:\/\/doi.org\/10.1021\/acs.jcim.5b00057","journal-title":"J Chem Inf Model"},{"key":"348_CR22","doi-asserted-by":"publisher","first-page":"348","DOI":"10.1002\/jcc.23804","volume":"36","author":"V Gapsys","year":"2015","unstructured":"Gapsys V, Michielssens S, Seeliger D, De Groot BL (2015) pmx: automated protein structure and topology generation for alchemical perturbations. J Comput Chem 36:348\u2013354. \n                    https:\/\/doi.org\/10.1002\/jcc.23804","journal-title":"J Comput Chem"},{"key":"348_CR23","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1016\/S1093-3263(98)80006-5","volume":"16","author":"J Marelius","year":"1998","unstructured":"Marelius J, Kolmodin K, Feierberg I et al (1998) Q: a molecular dynamics program for free energy calculations and empirical valence bond simulations in biomolecular systems. J Mol Graph Model 16:213\u2013225. \n                    https:\/\/doi.org\/10.1016\/S1093-3263(98)80006-5","journal-title":"J Mol Graph Model"},{"key":"348_CR24","doi-asserted-by":"crossref","unstructured":"Bauer P, Barrozo A, Purg M et al (2018) Q6: a comprehensive toolkit for empirical valence bond and related free energy calculations. SoftwareX","DOI":"10.1016\/j.softx.2017.12.001"},{"key":"348_CR25","doi-asserted-by":"publisher","first-page":"3100","DOI":"10.1063\/1.462997","volume":"97","author":"F Lee","year":"1992","unstructured":"Lee F, Warshel A (1992) A local reaction field method for fast evaluation of long-range electrostatic interactions in molecular simulations. J Chem Phys 97:3100\u20133107","journal-title":"J Chem Phys"},{"key":"348_CR26","doi-asserted-by":"publisher","first-page":"7822","DOI":"10.1039\/c7cc00980a","volume":"113","author":"GV Isaksen","year":"2016","unstructured":"Isaksen GV, \u00c5qvist J, Brandsdal BO (2016) Enzyme surface rigidity tunes the temperature dependence of catalytic rates. Proc Natl Acad Sci 113:7822\u20137827. \n                    https:\/\/doi.org\/10.1039\/c7cc00980a","journal-title":"Proc Natl Acad Sci"},{"key":"348_CR27","doi-asserted-by":"publisher","first-page":"10049","DOI":"10.1021\/bi801177k","volume":"47","author":"S Bjelic","year":"2008","unstructured":"Bjelic S, Brandsdal BO, \u00c5qvist J (2008) Cold adaptation of enzyme reaction rates. Biochemistry 47:10049\u201310057. \n                    https:\/\/doi.org\/10.1021\/bi801177k","journal-title":"Biochemistry"},{"key":"348_CR28","doi-asserted-by":"publisher","first-page":"849","DOI":"10.1021\/bi00507a030","volume":"20","author":"R Wolfenden","year":"1981","unstructured":"Wolfenden R, Andersson L, Cullis PM, Southgate CCB (1981) Affinities of amino acid side chains for solvent water. Biochemistry 20:849\u2013855. \n                    https:\/\/doi.org\/10.1021\/bi00507a030","journal-title":"Biochemistry"},{"key":"348_CR29","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1021\/acs.jctc.5b00864","volume":"12","author":"E Harder","year":"2016","unstructured":"Harder E, Damm W, Maple J et al (2016) OPLS3: a force field providing broad coverage of drug-like small molecules and proteins. J Chem Theory Comput 12:281\u2013296. \n                    https:\/\/doi.org\/10.1021\/acs.jctc.5b00864","journal-title":"J Chem Theory Comput"},{"key":"348_CR30","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1021\/acsomega.6b00086","volume":"1","author":"EB Lenselink","year":"2016","unstructured":"Lenselink EB, Louvel J, Forti AF et al (2016) Predicting binding affinities for GPCR ligands using free-energy perturbation. ACS Omega 1:293\u2013304. \n                    https:\/\/doi.org\/10.1021\/acsomega.6b00086","journal-title":"ACS Omega"},{"key":"348_CR31","doi-asserted-by":"publisher","first-page":"6887","DOI":"10.1021\/jm058018d","volume":"48","author":"P Minetti","year":"2005","unstructured":"Minetti P, Tinti MO, Carminati P et al (2005) 2-n-butyl-9-methyl-8-[1\u20133]triazol-2-yl-9H-purin-6-ylamine and analogues as A2A adenosine receptor antagonists. Design, synthesis, and pharmacological characterization. J Med Chem 48:6887\u20136896. \n                    https:\/\/doi.org\/10.1021\/jm058018d","journal-title":"J Med Chem"},{"key":"348_CR32","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1021\/acs.jctc.6b00991","volume":"13","author":"L Wang","year":"2017","unstructured":"Wang L, Deng Y, Wu Y et al (2017) Accurate modeling of scaffold hopping transformations in drug discovery. J Chem Theory Comput 13:42\u201354. \n                    https:\/\/doi.org\/10.1021\/acs.jctc.6b00991","journal-title":"J Chem Theory Comput"},{"key":"348_CR33","doi-asserted-by":"publisher","first-page":"3499","DOI":"10.1021\/acs.jctc.5b00356","volume":"11","author":"MJ Robertson","year":"2015","unstructured":"Robertson MJ, Tirado-Rives J, Jorgensen WL (2015) Improved peptide and protein torsional energetics with the OPLS-AA force field. J Chem Theory Comput 11:3499\u20133509. \n                    https:\/\/doi.org\/10.1021\/acs.jctc.5b00356","journal-title":"J Chem Theory Comput"},{"key":"348_CR34","doi-asserted-by":"publisher","first-page":"3696","DOI":"10.1021\/acs.jctc.5b00255","volume":"11","author":"JA Maier","year":"2015","unstructured":"Maier JA, Martinez C, Kasavajhala K et al (2015) ff14SB: improving the accuracy of protein side chain and backbone parameters from ff99SB. J Chem Theory Comput 11:3696\u20133713. \n                    https:\/\/doi.org\/10.1021\/acs.jctc.5b00255","journal-title":"J Chem Theory Comput"},{"key":"348_CR35","unstructured":"Purg M, Bauer P (2017) qtools v0.5.9"},{"key":"348_CR36","doi-asserted-by":"publisher","first-page":"U403","DOI":"10.1016\/j.jmgm.2005.12.005","volume":"222","author":"J Wang","year":"2001","unstructured":"Wang J, Wang W, Kollman PA, Case DA (2001) Antechamber, an accessory software package for molecular mechanical calculations. J Am Chem Soc 222:U403. \n                    https:\/\/doi.org\/10.1016\/j.jmgm.2005.12.005","journal-title":"J Am Chem Soc"},{"key":"348_CR37","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1002\/jcc.21367","volume":"31","author":"K Vanommeslaeghe","year":"2010","unstructured":"Vanommeslaeghe K, Hatcher E, Acharya C et al (2010) CHARMM general force field: a force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields. J Comput Chem 31:671\u2013690. \n                    https:\/\/doi.org\/10.1002\/jcc.21367","journal-title":"J Comput Chem"},{"key":"348_CR38","doi-asserted-by":"publisher","first-page":"1752","DOI":"10.1002\/jcc.20292","volume":"26","author":"JL Banks","year":"2005","unstructured":"Banks JL, Beard HS, Cao Y et al (2005) Integrated modeling program, applied chemical theory (IMPACT). J Comput Chem 26:1752\u20131780","journal-title":"J Comput Chem"},{"key":"348_CR39","doi-asserted-by":"publisher","unstructured":"Mobley DL, Bannan CC, Rizzi A et al (2018) Open Force Field Consortium: Escaping atom types using direct chemical perception with SMIRNOFF v0.1. bioRxiv 1\u201336. \n                    https:\/\/doi.org\/10.1101\/286542","DOI":"10.1101\/286542"},{"key":"348_CR40","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1007\/978-1-61779-465-0_20","volume":"819","author":"H Guti\u00e9rrez-De-Ter\u00e1n","year":"2012","unstructured":"Guti\u00e9rrez-De-Ter\u00e1n H, \u00c5qvist J (2012) Linear interaction energy: method and applications in drug design. Methods Mol Biol 819:305\u2013323. \n                    https:\/\/doi.org\/10.1007\/978-1-61779-465-0_20","journal-title":"Methods Mol Biol"},{"key":"348_CR41","doi-asserted-by":"publisher","first-page":"10235","DOI":"10.1021\/jp102971x","volume":"114","author":"A Pohorille","year":"2010","unstructured":"Pohorille A, Jarzynski C, Chipot C (2010) Good practices in free-energy calculations. J Phys Chem B 114:10235\u201310253. \n                    https:\/\/doi.org\/10.1021\/jp102971x","journal-title":"J Phys Chem B"},{"key":"348_CR42","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1016\/S0065-3233(03)66004-3","volume":"66","author":"BO Brandsdal","year":"2003","unstructured":"Brandsdal BO, \u00d6sterberg F, Alml\u00f6f M et al (2003) Free energy calculations and ligand binding. Adv Protein Chem 66:123\u2013158","journal-title":"Adv Protein Chem"},{"key":"348_CR43","doi-asserted-by":"publisher","first-page":"1420","DOI":"10.1063\/1.1740409","volume":"22","author":"RW Zwanzig","year":"1954","unstructured":"Zwanzig RW (1954) High-temperature equation of state by a perturbation method. I. Nonpolar gases. J Chem Phys 22:1420. \n                    https:\/\/doi.org\/10.1063\/1.1740409","journal-title":"J Chem Phys"},{"key":"348_CR44","doi-asserted-by":"publisher","first-page":"300","DOI":"10.1063\/1.1749657","volume":"3","author":"JG Kirkwood","year":"1935","unstructured":"Kirkwood JG (1935) Statistical mechanics of fluid mixtures. J Chem Phys 3:300\u2013313. \n                    https:\/\/doi.org\/10.1063\/1.1749657","journal-title":"J Chem Phys"},{"key":"348_CR45","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1016\/0021-9991(76)90078-4","volume":"22","author":"CH Bennett","year":"1976","unstructured":"Bennett CH (1976) Efficient estimation of free energy differences from Monte Carlo data. J Comput Phys 22:245\u2013268. \n                    https:\/\/doi.org\/10.1016\/0021-9991(76)90078-4","journal-title":"J Comput Phys"},{"key":"348_CR46","first-page":"3","volume":"1","author":"RA Fisher","year":"1921","unstructured":"Fisher RA (1921) On the \u201cprobable error\u201d of a coefficient of correlation deduced from a small sample. Metron 1:3\u201332","journal-title":"Metron"},{"key":"348_CR47","first-page":"2825","volume":"12","author":"F Pedregosa","year":"2011","unstructured":"Pedregosa F, Varoquaux G, Gramfort A et al (2011) Scikit-learn: machine learning in Python. J Mach Learn Res 12:2825\u20132830","journal-title":"J Mach Learn Res"},{"key":"348_CR48","unstructured":"Schr\u00f6dinger Release 2015-4"},{"key":"348_CR49","doi-asserted-by":"publisher","first-page":"1282","DOI":"10.1021\/ct300911a","volume":"9","author":"L Wang","year":"2013","unstructured":"Wang L, Deng Y, Knight JL et al (2013) Modeling local structural rearrangements using FEP\/REST: application to relative binding affinity predictions of CDK2 inhibitors. J Chem Theory Comput 9:1282\u20131293. \n                    https:\/\/doi.org\/10.1021\/ct300911a","journal-title":"J Chem Theory Comput"},{"key":"348_CR50","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1007\/s10822-013-9644-8","volume":"27","author":"G Madhavi Sastry","year":"2013","unstructured":"Madhavi Sastry G, 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":"348_CR51","doi-asserted-by":"publisher","first-page":"e108492","DOI":"10.1371\/journal.pone.0108492","volume":"9","author":"H Ker\u00e4nen","year":"2014","unstructured":"Ker\u00e4nen H, Guti\u00e9rrez-de-Ter\u00e1n H, \u00c5qvist J (2014) Structural and energetic effects of A2A adenosine receptor mutations on agonist and antagonist binding. PLoS ONE 9:e108492. \n                    https:\/\/doi.org\/10.1371\/journal.pone.0108492","journal-title":"PLoS ONE"},{"key":"348_CR52","doi-asserted-by":"publisher","first-page":"W455","DOI":"10.1093\/nar\/gkw403","volume":"44","author":"M Esguerra","year":"2016","unstructured":"Esguerra M, Siretskiy A, Bello X et al (2016) GPCR-ModSim: a comprehensive web based solution for modeling G-protein coupled receptors. Nucleic Acids Res 44:W455\u2013W462. \n                    https:\/\/doi.org\/10.1093\/nar\/gkw403","journal-title":"Nucleic Acids Res"},{"key":"348_CR53","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1042\/BST20120287","volume":"41","author":"H Guti\u00e9rrez-de-Ter\u00e1n","year":"2013","unstructured":"Guti\u00e9rrez-de-Ter\u00e1n H, Bello X, Rodr\u00edguez D (2013) Characterization of the dynamic events of GPCRs by automated computational simulations. Biochem Soc Trans 41:205\u2013212. \n                    https:\/\/doi.org\/10.1042\/BST20120287","journal-title":"Biochem Soc Trans"},{"key":"348_CR54","doi-asserted-by":"publisher","first-page":"3647","DOI":"10.1063\/1.456845","volume":"91","author":"G King","year":"1989","unstructured":"King G, Warshel A (1989) A surface constrained all-atom solvent model for effective simulations of polar solutions. J Chem Phys 91:3647. \n                    https:\/\/doi.org\/10.1063\/1.456845","journal-title":"J Chem Phys"},{"key":"348_CR55","doi-asserted-by":"publisher","first-page":"3100","DOI":"10.1063\/1.462997","volume":"97","author":"FS Lee","year":"1992","unstructured":"Lee FS, Warshel A (1992) A local reaction field method for fast evaluation of long-range electrostatic interactions in molecular simulations. J Chem Phys 97:3100. \n                    https:\/\/doi.org\/10.1063\/1.462997","journal-title":"J Chem Phys"},{"key":"348_CR56","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1016\/0021-9991(77)90098-5","volume":"23","author":"J-PJ Ryckaert","year":"1977","unstructured":"Ryckaert J-PJ, Ciccotti G, Berendsen HJH (1977) Numerical integration of the cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes. J Comput Phys 23:327\u2013341. \n                    https:\/\/doi.org\/10.1016\/0021-9991(77)90098-5","journal-title":"J Comput Phys"},{"key":"348_CR57","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1016\/0009-2614(94)00397-1","volume":"222","author":"TC Beutler","year":"1994","unstructured":"Beutler TC, Mark AE, van Schaik RC et al (1994) Avoiding singularities and numerical instabilities in free energy calculations based on molecular simulations. Chem Phys Lett 222:529\u2013539. \n                    https:\/\/doi.org\/10.1016\/0009-2614(94)00397-1","journal-title":"Chem Phys Lett"},{"key":"348_CR58","doi-asserted-by":"publisher","first-page":"8021","DOI":"10.1021\/j100384a009","volume":"94","author":"J \u00c5qvist","year":"1990","unstructured":"\u00c5qvist J (1990) Ion-water interaction potentials derived from free energy perturbation simulations. J Phys Chem 94:8021\u20138024. \n                    https:\/\/doi.org\/10.1021\/j100384a009","journal-title":"J Phys Chem"},{"key":"348_CR59","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1016\/j.drudis.2006.12.003","volume":"12","author":"H Zhao","year":"2007","unstructured":"Zhao H (2007) Scaffold selection and scaffold hopping in lead generation: a medicinal chemistry perspective. Drug Discov Today 12:149\u2013155","journal-title":"Drug Discov Today"},{"key":"348_CR60","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, Feeney PJ (1997) Experimental and computational approaches to estimate solubility and permeability in drug discovery and developmental settings. Adv Drug Deliv Rev 23:3\u201325. \n                    https:\/\/doi.org\/10.1016\/S0169-409X(96)00423-1","journal-title":"Adv Drug Deliv Rev"},{"key":"348_CR61","doi-asserted-by":"publisher","first-page":"150","DOI":"10.1016\/j.sbi.2011.01.011","volume":"21","author":"JD Chodera","year":"2011","unstructured":"Chodera JD, Mobley DL, Shirts MR et al (2011) Alchemical free energy methods for drug discovery: progress and challenges. Curr Opin Struct Biol 21:150\u2013160","journal-title":"Curr Opin Struct Biol"},{"key":"348_CR62","doi-asserted-by":"publisher","first-page":"2705","DOI":"10.1021\/acs.jpclett.7b01125","volume":"8","author":"H Zhang","year":"2017","unstructured":"Zhang H, Jiang Y, Yan H et al (2017) Free-energy calculations of ionic hydration consistent with the experimental hydration free energy of the proton. J Phys Chem Lett 8:2705\u20132712. \n                    https:\/\/doi.org\/10.1021\/acs.jpclett.7b01125","journal-title":"J Phys Chem Lett"},{"key":"348_CR63","doi-asserted-by":"publisher","first-page":"7787","DOI":"10.1021\/jp982638r","volume":"102","author":"MD Tissandier","year":"1998","unstructured":"Tissandier MD, Cowen KA, Feng WY et al (1998) The proton\u2019s absolute aqueous enthalpy and Gibbs free energy of solvation from cluster-ion solvation data. J Phys Chem A 102:7787\u20137794. \n                    https:\/\/doi.org\/10.1021\/jp982638r","journal-title":"J Phys Chem A"},{"key":"348_CR64","doi-asserted-by":"publisher","first-page":"16066","DOI":"10.1021\/jp063552y","volume":"110","author":"CP Kelly","year":"2006","unstructured":"Kelly CP, Cramer CJ, Truhlar DG (2006) Aqueous solvation free energies of ions and ion-water clusters based on an accurate value for the absolute aqueous solvation free energy of the proton. J Phys Chem B 110:16066\u201316081. \n                    https:\/\/doi.org\/10.1021\/jp063552y","journal-title":"J Phys Chem B"},{"key":"348_CR65","unstructured":"Marenich A, Kelly C, Thompson J, Hawkins G (2012) Minnesota solvation database. Minnesota Solvation Database version 20"},{"key":"348_CR66","doi-asserted-by":"publisher","first-page":"3692","DOI":"10.1021\/jp049914o","volume":"108","author":"MW Palascak","year":"2004","unstructured":"Palascak MW, Shields GC (2004) Accurate experimental values for the free energies of hydration of H+, OH\u2212, and H3O+. J Phys Chem A 108:3692\u20133694. \n                    https:\/\/doi.org\/10.1021\/jp049914o","journal-title":"J Phys Chem A"},{"key":"348_CR67","doi-asserted-by":"publisher","first-page":"2098","DOI":"10.1021\/jp0620163","volume":"111","author":"J Chang","year":"2007","unstructured":"Chang J, Lenhoff AM, Sandler SI (2007) Solvation free energy of amino acids and side-chain analogues. J Phys Chem B 111:2098\u20132106. \n                    https:\/\/doi.org\/10.1021\/jp0620163","journal-title":"J Phys Chem B"},{"key":"348_CR68","doi-asserted-by":"publisher","first-page":"5740","DOI":"10.1063\/1.1587119","volume":"119","author":"MR Shirts","year":"2003","unstructured":"Shirts MR, Pitera JW, Swope WC, Pande VS (2003) Extremely precise free energy calculations of amino acid side chain analogs: comparison of common molecular mechanics force fields for proteins. J Chem Phys 119:5740\u20135761. \n                    https:\/\/doi.org\/10.1063\/1.1587119","journal-title":"J Chem Phys"},{"key":"348_CR69","doi-asserted-by":"publisher","first-page":"1930","DOI":"10.1002\/jcc.10328","volume":"24","author":"JL Maccallum","year":"2003","unstructured":"Maccallum JL, Peter Tieleman D (2003) Calculation of the water-cyclohexane transfer free energies of neutral amino acid side-chain analogs using the OPLS all-atom force field. J Comput Chem 24:1930\u20131935. \n                    https:\/\/doi.org\/10.1002\/jcc.10328","journal-title":"J Comput Chem"},{"key":"348_CR70","doi-asserted-by":"publisher","first-page":"1559","DOI":"10.1021\/acs.jced.7b00104","volume":"62","author":"G Duarte Ramos Matos","year":"2017","unstructured":"Duarte Ramos Matos G, Kyu DY, Loeffler HH et al (2017) Approaches for calculating solvation free energies and enthalpies demonstrated with an update of the FreeSolv database. J Chem Eng Data 62:1559\u20131569","journal-title":"J Chem Eng Data"},{"key":"348_CR71","doi-asserted-by":"publisher","first-page":"3710","DOI":"10.1021\/jm0311442","volume":"47","author":"IR Hardcastle","year":"2004","unstructured":"Hardcastle IR, Arris CE, Bentley J et al (2004) N2-substituted O6-cyclohexylmethylguanine derivatives: potent inhibitors of cyclin-dependent kinases 1 and 2. J Med Chem 47:3710\u20133722. \n                    https:\/\/doi.org\/10.1021\/jm0311442","journal-title":"J Med Chem"},{"key":"348_CR72","doi-asserted-by":"publisher","first-page":"40","DOI":"10.2174\/1568026616666160719164207","volume":"17","author":"H Guti\u00e9rrez-de-Ter\u00e1n","year":"2017","unstructured":"Guti\u00e9rrez-de-Ter\u00e1n H, Sallander J, Sotelo E (2017) Structure-based rational design of adenosine receptor ligands. Curr Top Med Chem 17:40\u201358. \n                    https:\/\/doi.org\/10.2174\/1568026616666160719164207","journal-title":"Curr Top Med Chem"},{"key":"348_CR73","doi-asserted-by":"publisher","first-page":"10049","DOI":"10.1021\/bi801177k","volume":"47","author":"S Bjelic","year":"2008","unstructured":"Bjelic S, Brandsdal BO, \u00c5qvist J (2008) Cold adaptation of enzyme reaction rates. Biochemistry 47:10049\u201310057. \n                    https:\/\/doi.org\/10.1021\/bi801177k","journal-title":"Biochemistry"},{"key":"348_CR74","doi-asserted-by":"publisher","first-page":"7502","DOI":"10.1021\/acs.jmedchem.7b00860","volume":"60","author":"J Azuaje","year":"2017","unstructured":"Azuaje J, Jespers W, Yaziji V et al (2017) Effect of nitrogen atom substitution in A3 adenosine receptor binding: N-(4,6-diarylpyridin-2-yl)acetamides as potent and selective antagonists. J Med Chem 60:7502\u20137511. \n                    https:\/\/doi.org\/10.1021\/acs.jmedchem.7b00860","journal-title":"J Med Chem"},{"key":"348_CR75","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1126\/science.1219218","volume":"337","author":"W Liu","year":"2012","unstructured":"Liu W, Chun E, Thompson AA et al (2012) Structural basis for allosteric regulation of GPCRs by sodium ions. Science 337:232\u2013236. \n                    https:\/\/doi.org\/10.1126\/science.1219218","journal-title":"Science"},{"key":"348_CR76","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/j.tips.2017.11.001","volume":"39","author":"W Jespers","year":"2018","unstructured":"Jespers W, Schiedel AC, Heitman LH et al (2018) Structural mapping of adenosine receptor mutations: ligand binding and signaling mechanisms. Trends Pharmacol Sci 39:75\u201389","journal-title":"Trends Pharmacol Sci"},{"key":"348_CR77","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1016\/j.ddtec.2004.10.009","volume":"1","author":"HJ B\u00f6hm","year":"2004","unstructured":"B\u00f6hm HJ, Flohr A, Stahl M (2004) Scaffold hopping. Drug Discov Today Technol 1:217\u2013224. \n                    https:\/\/doi.org\/10.1016\/j.ddtec.2004.10.009","journal-title":"Drug Discov Today Technol"},{"key":"348_CR78","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1021\/acs.jctc.6b00991","volume":"13","author":"L Wang","year":"2017","unstructured":"Wang L, Deng Y, Wu Y et al (2017) Accurate modeling of scaffold hopping transformations in drug discovery. J Chem Theory Comput 13:42\u201354. \n                    https:\/\/doi.org\/10.1021\/acs.jctc.6b00991","journal-title":"J Chem Theory Comput"}],"container-title":["Journal of Cheminformatics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s13321-019-0348-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/s13321-019-0348-5\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s13321-019-0348-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,3,31]],"date-time":"2020-03-31T23:13:23Z","timestamp":1585696403000},"score":1,"resource":{"primary":{"URL":"https:\/\/jcheminf.biomedcentral.com\/articles\/10.1186\/s13321-019-0348-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,4,2]]},"references-count":78,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2019,12]]}},"alternative-id":["348"],"URL":"https:\/\/doi.org\/10.1186\/s13321-019-0348-5","relation":{},"ISSN":["1758-2946"],"issn-type":[{"value":"1758-2946","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,4,2]]},"assertion":[{"value":"20 December 2018","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 March 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 April 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"26"}}