{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T23:44:39Z","timestamp":1793403879890,"version":"4.5.0"},"reference-count":63,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,8,19]],"date-time":"2021-08-19T00:00:00Z","timestamp":1629331200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,8,19]],"date-time":"2021-08-19T00:00:00Z","timestamp":1629331200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100009082","name":"Universidad Cat\u00f3lica de C\u00f3rdoba","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009082","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006668","name":"Fondo para la Investigaci\u00f3n Cient\u00edfica y Tecnol\u00f3gica","doi-asserted-by":"publisher","award":["PICT 2014-1594"],"award-info":[{"award-number":["PICT 2014-1594"]}],"id":[{"id":"10.13039\/501100006668","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006668","name":"Fondo para la Investigaci\u00f3n Cient\u00edfica y Tecnol\u00f3gica","doi-asserted-by":"publisher","award":["PICT 2015-1769"],"award-info":[{"award-number":["PICT 2015-1769"]}],"id":[{"id":"10.13039\/501100006668","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006668","name":"Fondo para la Investigaci\u00f3n Cient\u00edfica y Tecnol\u00f3gica","doi-asserted-by":"publisher","award":["PICT 2015-1769"],"award-info":[{"award-number":["PICT 2015-1769"]}],"id":[{"id":"10.13039\/501100006668","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006668","name":"Fondo para la Investigaci\u00f3n Cient\u00edfica y Tecnol\u00f3gica","doi-asserted-by":"publisher","award":["PICT 2014-1594"],"award-info":[{"award-number":["PICT 2014-1594"]}],"id":[{"id":"10.13039\/501100006668","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014440","name":"Ministerio de Ciencia, Innovaci\u00f3n y Universidades","doi-asserted-by":"publisher","award":["project #RTI2018-098560-B-C22"],"award-info":[{"award-number":["project #RTI2018-098560-B-C22"]}],"id":[{"id":"10.13039\/100014440","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014440","name":"Ministerio de Ciencia, Innovaci\u00f3n y Universidades","doi-asserted-by":"publisher","award":["project #RTI2018-098560-B-C22"],"award-info":[{"award-number":["project #RTI2018-098560-B-C22"]}],"id":[{"id":"10.13039\/100014440","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010268","name":"Consejo Nacional para Investigaciones Cient\u00edficas y Tecnol\u00f3gicas","doi-asserted-by":"publisher","award":["PIP 2014-2016"],"award-info":[{"award-number":["PIP 2014-2016"]}],"id":[{"id":"10.13039\/501100010268","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>P-gp-associated multidrug resistance is a major impediment to the success of chemotherapy. With the aim of finding non-toxic and effective P-gp inhibitors, we investigated a panel of quinolin-2-one-pyrimidine hybrids. Among the active compounds, two of them significantly increased intracellular doxorubicin and rhodamine 123 accumulation by inhibiting the efflux mediated by P-gp and restored doxorubicin toxicity at nanomolar range. Structure\u2013activity relationships showed that the number of methoxy groups, an optimal length of the molecule in its extended conformation, and at least one flexible methylene group bridging the quinolinone to the moiety bearing the pyrimidine favored the inhibitory potency of P-gp. The best compounds showed a similar binding pattern and interactions to those of doxorubicin and tariquidar, as revealed by MD and hybrid QM\/MM simulations performed with the recent experimental structure of P-gp co-crystallized with paclitaxel. Analysis of the molecular interactions stabilizing the different molecular complexes determined by MD and QTAIM showed that binding to key residues from TMH 4\u20137 and 12 is required for inhibition.<\/jats:p>","DOI":"10.1038\/s41598-021-96226-6","type":"journal-article","created":{"date-parts":[[2021,8,19]],"date-time":"2021-08-19T06:30:05Z","timestamp":1629354605000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Structure activity relationships and the binding mode of quinolinone-pyrimidine hybrids as reversal agents of multidrug resistance mediated by P-gp"],"prefix":"10.1038","volume":"11","author":[{"given":"Jer\u00f3nimo","family":"Laiolo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priscila Ailin","family":"Lanza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oscar","family":"Parravicini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecilia","family":"Barbieri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Insuasty","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justo","family":"Cobo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. Mariano Adolfo","family":"Vera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ricardo Daniel","family":"Enriz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Cecilia","family":"Carpinella","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,8,19]]},"reference":[{"key":"96226_CR1","doi-asserted-by":"publisher","first-page":"888","DOI":"10.1016\/j.fct.2017.04.039","volume":"109","author":"MB Joray","year":"2017","unstructured":"Joray, M. B. et al. P53 tumor suppressor is required for efficient execution of the death program following treatment with a cytotoxic limonoid obtained from Melia azedarach. Food Chem. Toxicol. 109, 888\u2013897 (2017).","journal-title":"Food Chem. Toxicol."},{"key":"96226_CR2","doi-asserted-by":"publisher","first-page":"100681","DOI":"10.1016\/j.drup.2020.100681","volume":"49","author":"J Dong","year":"2020","unstructured":"Dong, J. et al. Medicinal chemistry strategies to discover P-glycoprotein inhibitors: An update. Drug Resist. Updat. 49, 100681 (2020).","journal-title":"Drug Resist. Updat."},{"key":"96226_CR3","doi-asserted-by":"publisher","first-page":"1909","DOI":"10.1021\/acs.jnatprod.0c00115","volume":"83","author":"MF Garc\u00eda Manzano","year":"2020","unstructured":"Garc\u00eda Manzano, M. F., Joray, M. B., Laiolo, J., Palacios, S. M. & Carpinella, M. C. Cytotoxic activity of germacrane-type sesquiterpene lactones from Dimerostemma aspilioides. J. Nat. Prod. 83, 1909\u20131918 (2020).","journal-title":"J. Nat. Prod."},{"key":"96226_CR4","doi-asserted-by":"publisher","first-page":"6556","DOI":"10.1038\/s41598-021-86120-6","volume":"11","author":"R Kubiliute","year":"2021","unstructured":"Kubiliute, R. et al. Nongenotoxic ABCB1 activator tetraphenylphosphonium can contribute to doxorubicin resistance in MX-1 breast cancer cell line. Sci. Rep. 11, 6556 (2021).","journal-title":"Sci. Rep."},{"key":"96226_CR5","doi-asserted-by":"publisher","first-page":"205","DOI":"10.3389\/fphar.2017.00205","volume":"8","author":"ML Gonz\u00e1lez","year":"2017","unstructured":"Gonz\u00e1lez, M. L. et al. Mechanism underlying the reversal of drug resistance in P-glycoprotein-expressing leukemia cells by pinoresinol and the study of a derivative. Front. Pharmacol. 8, 205 (2017).","journal-title":"Front. Pharmacol."},{"key":"96226_CR6","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41598-018-32770-y","volume":"8","author":"I Guberovi\u0107","year":"2018","unstructured":"Guberovi\u0107, I. et al. Crown ethers reverse P-glycoprotein-mediated multidrug resistance in cancer cells. Sci. Rep. 8, 1\u201314 (2018).","journal-title":"Sci. Rep."},{"key":"96226_CR7","doi-asserted-by":"publisher","first-page":"3233","DOI":"10.3390\/ijms21093233","volume":"21","author":"K Bukowski","year":"2020","unstructured":"Bukowski, K., Kciuk, M. & Kontek, R. Mechanisms of multidrug resistance in cancer chemotherapy. Int. J. Mol. Sci. 21, 3233 (2020).","journal-title":"Int. J. Mol. Sci."},{"key":"96226_CR8","doi-asserted-by":"publisher","first-page":"111922","DOI":"10.1016\/j.fct.2020.111922","volume":"147","author":"J Laiolo","year":"2021","unstructured":"Laiolo, J. et al. Plant extracts and betulin from Ligaria cuneifolia inhibit P-glycoprotein function in leukemia cells. Food Chem. Toxicol. 147, 111922 (2021).","journal-title":"Food Chem. Toxicol."},{"key":"96226_CR9","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41598-020-66587-5","volume":"10","author":"CA Bonito","year":"2020","unstructured":"Bonito, C. A. et al. Theoretical insights on helix repacking as the origin of P-glycoprotein promiscuity. Sci. Rep. 10, 1\u201313 (2020).","journal-title":"Sci. Rep."},{"key":"96226_CR10","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41598-016-0028-x","volume":"7","author":"SB Syed","year":"2017","unstructured":"Syed, S. B. et al. Targeting P-glycoprotein: Investigation of piperine analogs for overcoming drug resistance in cancer. Sci. Rep. 7, 1\u201318 (2017).","journal-title":"Sci. Rep."},{"key":"96226_CR11","doi-asserted-by":"publisher","first-page":"546","DOI":"10.1016\/j.tips.2009.07.003","volume":"30","author":"MD Hall","year":"2009","unstructured":"Hall, M. D., Handley, M. D. & Gottesman, M. M. Is resistance useless? Multidrug resistance and collateral sensitivity. Trends Pharmacol. Sci. 30, 546\u2013556 (2009).","journal-title":"Trends Pharmacol. Sci."},{"key":"96226_CR12","doi-asserted-by":"publisher","first-page":"967","DOI":"10.1038\/s41598-018-19325-x","volume":"8","author":"AK Nanayakkara","year":"2018","unstructured":"Nanayakkara, A. K. et al. Targeted inhibitors of P-glycoprotein increase chemotherapeutic-induced mortality of multidrug resistant tumor cells. Sci. Rep. 8, 967 (2018).","journal-title":"Sci. Rep."},{"key":"96226_CR13","doi-asserted-by":"publisher","first-page":"103083","DOI":"10.1016\/j.bioorg.2019.103083","volume":"90","author":"Q Qiu","year":"2019","unstructured":"Qiu, Q. et al. Discovery of aromatic amides with triazole-core as potent reversal agents against P-glycoprotein-mediated multidrug resistance. Bioorg. Chem. 90, 103083 (2019).","journal-title":"Bioorg. Chem."},{"key":"96226_CR14","doi-asserted-by":"publisher","first-page":"6857","DOI":"10.1016\/j.bmc.2014.10.032","volume":"22","author":"L Jiao","year":"2014","unstructured":"Jiao, L. et al. Design, synthesis and evaluation of novel triazole core based P-glycoprotein-mediated multidrug resistance reversal agents. Bioorg. Med. Chem. 22, 6857\u20136866 (2014).","journal-title":"Bioorg. Med. Chem."},{"key":"96226_CR15","doi-asserted-by":"publisher","first-page":"100682","DOI":"10.1016\/j.drup.2020.100682","volume":"50","author":"S Dallavalle","year":"2020","unstructured":"Dallavalle, S. et al. Improvement of conventional anti-cancer drugs as new tools against multidrug resistant tumors. Drug Resist. Updat. 50, 100682 (2020).","journal-title":"Drug Resist. Updat."},{"key":"96226_CR16","doi-asserted-by":"publisher","first-page":"112458","DOI":"10.1016\/j.ejmech.2020.112458","volume":"200","author":"Z-X He","year":"2020","unstructured":"He, Z.-X. et al. Pyrimidine: A promising scaffold for optimization to develop the inhibitors of ABC transporters. Eur. J. Med. Chem. 200, 112458 (2020).","journal-title":"Eur. J. Med. Chem."},{"key":"96226_CR17","doi-asserted-by":"publisher","first-page":"103414","DOI":"10.1016\/j.bioorg.2019.103414","volume":"94","author":"M Vettorazzi","year":"2020","unstructured":"Vettorazzi, M. et al. Design of new quinolin-2-one-pyrimidine hybrids as sphingosine kinases inhibitors. Bioorg. Chem. 94, 103414 (2020).","journal-title":"Bioorg. Chem."},{"key":"96226_CR18","doi-asserted-by":"publisher","first-page":"112843","DOI":"10.1016\/j.ejmech.2020.112843","volume":"208","author":"M Contino","year":"2020","unstructured":"Contino, M. et al. One molecule two goals: A selective P-glycoprotein modulator increases drug transport across gastro-intestinal barrier and recovers doxorubicin toxicity in multidrug resistant cancer cells. Eur. J. Med. Chem. 208, 112843 (2020).","journal-title":"Eur. J. Med. Chem."},{"key":"96226_CR19","doi-asserted-by":"publisher","first-page":"2420","DOI":"10.1016\/j.bmc.2018.03.045","volume":"26","author":"Y Gao","year":"2018","unstructured":"Gao, Y. et al. Design, synthesis and biological evaluation of novel tetrahydroisoquinoline derivatives as P-glycoprotein-mediated multidrug resistance inhibitors. Bioorg. Med. Chem. 26, 2420\u20132427 (2018).","journal-title":"Bioorg. Med. Chem."},{"key":"96226_CR20","doi-asserted-by":"publisher","first-page":"3347","DOI":"10.1016\/j.bmc.2019.06.013","volume":"27","author":"M Kairuki","year":"2019","unstructured":"Kairuki, M. et al. Designed P-glycoprotein inhibitors with triazol-tetrahydroisoquinoline-core increase doxorubicin-induced mortality in multidrug resistant K562\/A02 cells. Bioorg. Med. Chem. 27, 3347\u20133357 (2019).","journal-title":"Bioorg. Med. Chem."},{"key":"96226_CR21","doi-asserted-by":"publisher","first-page":"974","DOI":"10.1021\/acs.jmedchem.8b01655","volume":"62","author":"C Riganti","year":"2019","unstructured":"Riganti, C. et al. Design, biological evaluation, and molecular modeling of tetrahydroisoquinoline derivatives: Discovery of A Potent P-Glycoprotein ligand overcoming multidrug resistance in cancer stem cells. J. Med. Chem. 62, 974\u2013986 (2019).","journal-title":"J. Med. Chem."},{"key":"96226_CR22","doi-asserted-by":"publisher","first-page":"1900127","DOI":"10.1002\/ardp.201900127","volume":"352","author":"Q Qiu","year":"2019","unstructured":"Qiu, Q. et al. Discovery to solve multidrug resistance: Design, synthesis, and biological evaluation of novel agents. Arch. Pharm. 352, 1900127 (2019).","journal-title":"Arch. Pharm."},{"key":"96226_CR23","doi-asserted-by":"publisher","first-page":"4395","DOI":"10.1016\/j.tetlet.2014.05.094","volume":"55","author":"KK Laali","year":"2014","unstructured":"Laali, K. K., Insuasty, D., Abonia, R., Insuasty, B. & Bunge, S. D. Novel quinoline\u2013imidazolium adducts via the reaction of 2-oxoquinoline-3-carbaldehyde and quinoline-3-carbaldehydes with 1-butyl-3-methylimidazolium chloride [BMIM][Cl]. Tetrahedron Lett. 55, 4395\u20134399 (2014).","journal-title":"Tetrahedron Lett."},{"key":"96226_CR24","doi-asserted-by":"publisher","first-page":"4415","DOI":"10.1016\/j.tetlet.2006.04.082","volume":"47","author":"SC Ceide","year":"2006","unstructured":"Ceide, S. C. & Montalban, A. G. Microwave-assisted, efficient and regioselective Pd-catalyzed C-phenylation of halopyrimidines. Tetrahedron Lett. 47, 4415\u20134418 (2006).","journal-title":"Tetrahedron Lett."},{"key":"96226_CR25","doi-asserted-by":"publisher","first-page":"2404","DOI":"10.1016\/j.bmcl.2008.02.056","volume":"18","author":"B Mavunkel","year":"2008","unstructured":"Mavunkel, B. et al. Pyrimidine-based inhibitors of CaMKII\u03b4. Bioorg. Med. Chem. Lett. 18, 2404\u20132408 (2008).","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"96226_CR26","doi-asserted-by":"publisher","first-page":"112331","DOI":"10.1016\/j.ejmech.2020.112331","volume":"198","author":"M Sagnou","year":"2020","unstructured":"Sagnou, M. et al. Novel curcumin derivatives as P-glycoprotein inhibitors: Molecular modeling, synthesis and sensitization of multidrug resistant cells to doxorubicin. Eur. J. Med. Chem. 198, 112331 (2020).","journal-title":"Eur. J. Med. Chem."},{"key":"96226_CR27","doi-asserted-by":"publisher","first-page":"112985","DOI":"10.1016\/j.ejmech.2020.112985","volume":"210","author":"DS Cardoso","year":"2021","unstructured":"Cardoso, D. S. et al. Alkylated monoterpene indole alkaloid derivatives as potent P-glycoprotein inhibitors in resistant cancer cells. Eur. J. Med. Chem. 210, 112985 (2021).","journal-title":"Eur. J. Med. Chem."},{"key":"96226_CR28","doi-asserted-by":"publisher","first-page":"1078","DOI":"10.1194\/jlr.M091876","volume":"60","author":"S-F Tan","year":"2019","unstructured":"Tan, S.-F. et al. Acid ceramidase promotes drug resistance in acute myeloid leukemia through NF-\u03baB-dependent P-glycoprotein upregulation. J. Lipid Res. 60, 1078\u20131086 (2019).","journal-title":"J. Lipid Res."},{"key":"96226_CR29","doi-asserted-by":"publisher","first-page":"1203","DOI":"10.1111\/j.1471-4159.2006.04295.x","volume":"100","author":"A Pilorget","year":"2007","unstructured":"Pilorget, A. et al. Modulation of P-glycoprotein function by sphingosine kinase-1 in brain endothelial cells. J. Neurochem. 100, 1203\u20131210 (2007).","journal-title":"J. Neurochem."},{"key":"96226_CR30","doi-asserted-by":"publisher","first-page":"107554","DOI":"10.1016\/j.pharmthera.2020.107554","volume":"213","author":"E Gil-Martins","year":"2020","unstructured":"Gil-Martins, E., Barbosa, D. J., Silva, V., Remi\u00e3o, F. & Silva, R. Dysfunction of ABC transporters at the blood-brain barrier: Role in neurological disorders. Pharmacol. Ther. 213, 107554 (2020).","journal-title":"Pharmacol. Ther."},{"key":"96226_CR31","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1016\/j.ejmech.2012.05.026","volume":"54","author":"J Yuan","year":"2012","unstructured":"Yuan, J. et al. Synthesis of methylated quercetin derivatives and their reversal activities on P-gp- and BCRP-mediated multidrug resistance tumour cells. Eur. J. Med. Chem. 54, 413\u2013422 (2012).","journal-title":"Eur. J. Med. Chem."},{"key":"96226_CR32","doi-asserted-by":"publisher","first-page":"558","DOI":"10.1016\/j.ejmech.2014.02.051","volume":"76","author":"G Nesi","year":"2014","unstructured":"Nesi, G. et al. SAR study on arylmethyloxyphenyl scaffold: Looking for a P-gp nanomolar affinity. Eur. J. Med. Chem. 76, 558\u2013566 (2014).","journal-title":"Eur. J. Med. Chem."},{"key":"96226_CR33","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1002\/med.21739","volume":"41","author":"H Zhang","year":"2020","unstructured":"Zhang, H. et al. Chemical molecular-based approach to overcome multidrug resistance in cancer by targeting P-glycoprotein (P-gp). Med. Res. Rev. 41, 525\u2013555 (2020).","journal-title":"Med. Res. Rev."},{"key":"96226_CR34","doi-asserted-by":"publisher","first-page":"753","DOI":"10.1126\/science.aav7102","volume":"363","author":"A Alam","year":"2019","unstructured":"Alam, A., Kowal, J., Broude, E., Roninson, I. & Locher, K. P. Structural insight into substrate and inhibitor discrimination by human P-glycoprotein. Science 363, 753 (2019).","journal-title":"Science"},{"key":"96226_CR35","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/j.jmgm.2013.09.001","volume":"46","author":"GE Jara","year":"2013","unstructured":"Jara, G. E., Vera, D. M. A. & Pierini, A. B. Binding of modulators to mouse and human multidrug resistance P-glycoprotein. A computational study. J. Mol. Graph. Model. 46, 10\u201321 (2013).","journal-title":"J. Mol. Graph. Model."},{"key":"96226_CR36","doi-asserted-by":"publisher","first-page":"5988","DOI":"10.1021\/acs.jmedchem.8b00335","volume":"61","author":"B Wang","year":"2018","unstructured":"Wang, B. et al. Discovery of 5-cyano-6-phenylpyrimidin derivatives containing an acylurea moiety as orally bioavailable reversal agents against P-glycoprotein-mediated mutidrug resistance. J. Med. Chem. 61, 5988\u20136001 (2018).","journal-title":"J. Med. Chem."},{"key":"96226_CR37","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1007\/s13346-018-0584-7","volume":"9","author":"M Pa\u0161kevi\u010di\u016bt\u0117","year":"2019","unstructured":"Pa\u0161kevi\u010di\u016bt\u0117, M. & Petrikait\u0117, V. Overcoming transporter-mediated multidrug resistance in cancer: Failures and achievements of the last decades. Drug Deliv. Transl. Res. 9, 379\u2013393 (2019).","journal-title":"Drug Deliv. Transl. Res."},{"key":"96226_CR38","first-page":"2336","volume":"10","author":"J-I Lai","year":"2020","unstructured":"Lai, J.-I., Chen, M.-H., Huang, C.-Y.F. & Chang, M.-H. Clinical perspective of FDA approved drugs with p-glycoprotein inhibition activities for potential cancer therapeutics. Front. Oncol. 10, 2336 (2020).","journal-title":"Front. Oncol."},{"key":"96226_CR39","doi-asserted-by":"publisher","first-page":"1186","DOI":"10.1021\/acsmedchemlett.8b00324","volume":"9","author":"J Laiolo","year":"2018","unstructured":"Laiolo, J. et al. Analogues of the lignan pinoresinol as novel lead compounds for P-glycoprotein (P-gp) inhibitors. ACS Med. Chem. Lett. 9, 1186\u20131192 (2018).","journal-title":"ACS Med. Chem. Lett."},{"key":"96226_CR40","doi-asserted-by":"publisher","first-page":"26245","DOI":"10.1073\/pnas.2010264117","volume":"117","author":"K Nosol","year":"2020","unstructured":"Nosol, K. et al. Cryo-EM structures reveal distinct mechanisms of inhibition of the human multidrug transporter ABCB1. Proc. Natl. Acad. Sci. 117, 26245\u201326253 (2020).","journal-title":"Proc. Natl. Acad. Sci."},{"key":"96226_CR41","unstructured":"Anyway, the in silico structure of tariquidar obtained in the present work, overlaps with the region of contact of both molecules, in particular with one of them, it sharing the residues Leu65, Trp232, Leu236, Ile299, Phe303, Ile306, Tyr307, Phe 336, Ile 340, Phe343, Gln347, Gln725, Phe728, Phe732, Val835, Met876, Phe983, Met986, Gln990 and Val991."},{"key":"96226_CR42","doi-asserted-by":"publisher","first-page":"112792","DOI":"10.1016\/j.ejmech.2020.112792","volume":"208","author":"S Rojas","year":"2020","unstructured":"Rojas, S. et al. Combined MD\/QTAIM techniques to evaluate ligand-receptor interactions. Scope and limitations. Eur. J. Med. Chem. 208, 112792 (2020).","journal-title":"Eur. J. Med. Chem."},{"key":"96226_CR43","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1021\/ci2004225","volume":"52","author":"SA Andujar","year":"2012","unstructured":"Andujar, S. A. et al. Searching the \u201cbiologically relevant\u201d conformation of dopamine: A computational approach. J. Chem. Inf. Model. 52, 99\u2013112 (2012).","journal-title":"J. Chem. Inf. Model."},{"key":"96226_CR44","doi-asserted-by":"publisher","first-page":"2018","DOI":"10.1021\/ci400178h","volume":"53","author":"RD Tosso","year":"2013","unstructured":"Tosso, R. D. et al. Molecular modeling study of dihydrofolate reductase inhibitors. Molecular dynamics simulations, quantum mechanical calculations, and experimental corroboration. J. Chem. Inf. Model. 53, 2018\u20132032 (2013).","journal-title":"J. Chem. Inf. Model."},{"key":"96226_CR45","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1016\/j.ejmech.2017.08.017","volume":"139","author":"M Vettorazzi","year":"2017","unstructured":"Vettorazzi, M. et al. An integrative study to identify novel scaffolds for sphingosine kinase 1 inhibitors. Eur. J. Med. Chem. 139, 461\u2013481 (2017).","journal-title":"Eur. J. Med. Chem."},{"key":"96226_CR46","doi-asserted-by":"publisher","first-page":"781","DOI":"10.1007\/s10822-018-0129-7","volume":"32","author":"M Vettorazzi","year":"2018","unstructured":"Vettorazzi, M. et al. Theoretical models to predict the inhibitory effect of ligands of sphingosine kinase 1 using QTAIM calculations and hydrogen bond dynamic propensity analysis. J. Comput. Aided Mol. Des. 32, 781\u2013791 (2018).","journal-title":"J. Comput. Aided Mol. Des."},{"key":"96226_CR47","doi-asserted-by":"publisher","first-page":"1898","DOI":"10.1002\/jcc.26361","volume":"41","author":"RD Tosso","year":"2020","unstructured":"Tosso, R. D. et al. Conformational and electronic study of dopamine interacting with the D2 dopamine receptor. J. Comput. Chem. 41, 1898\u20131911 (2020).","journal-title":"J. Comput. Chem."},{"key":"96226_CR48","doi-asserted-by":"publisher","first-page":"3349","DOI":"10.1021\/jp060571z","volume":"110","author":"R Parthasarathi","year":"2006","unstructured":"Parthasarathi, R., Subramanian, V. & Sathyamurthy, N. Hydrogen bonding without borders: An atoms-in-molecules perspective. J. Phys. Chem. A 110, 3349\u20133351 (2006).","journal-title":"J. Phys. Chem. A"},{"key":"96226_CR49","doi-asserted-by":"publisher","first-page":"983","DOI":"10.1016\/j.leukres.2014.06.001","volume":"38","author":"MAM Moreira","year":"2014","unstructured":"Moreira, M. A. M. et al. Changes in gene expression profile in two multidrug resistant cell lines derived from a same drug sensitive cell line. Leuk. Res. 38, 983\u2013987 (2014).","journal-title":"Leuk. Res."},{"key":"96226_CR50","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1155\/2015\/912484","volume":"2015","author":"MB Joray","year":"2015","unstructured":"Joray, M. B. et al. Antibacterial and cytotoxic activity of compounds isolated from Flourensia oolepis. Evid. Based Complement. Alternat. Med. 2015, 11 (2015).","journal-title":"Evid. Based Complement. Alternat. Med."},{"key":"96226_CR51","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1016\/j.fct.2019.01.019","volume":"125","author":"MI Crespo","year":"2019","unstructured":"Crespo, M. I. et al. Inhibitory effects of compounds isolated from Lepechinia meyenii on tyrosinase. Food Chem. Toxicol. 125, 383\u2013391 (2019).","journal-title":"Food Chem. Toxicol."},{"key":"96226_CR52","unstructured":"Gaussian 16, Revision A.03, Frisch, M. J. et al. (Gaussian, Inc., Wallingford CT, 2016)."},{"key":"96226_CR53","doi-asserted-by":"publisher","first-page":"2785","DOI":"10.1002\/jcc.21256","volume":"16","author":"GM Morris","year":"2009","unstructured":"Morris, G. M. et al. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J. Comput. Chem. 16, 2785\u20132791 (2009).","journal-title":"J. Comput. Chem."},{"key":"96226_CR54","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","volume":"31","author":"O Trott","year":"2010","unstructured":"Trott, O. & Olson, A. J. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem. 31, 455\u2013461 (2010).","journal-title":"J. Comput. Chem."},{"key":"96226_CR55","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1016\/j.jmgm.2005.12.005","volume":"25","author":"J Wang","year":"2006","unstructured":"Wang, J., Wang, W., Kollman, P. A. & Case, D. A. Automatic atom type and bond type perception in molecular mechanical calculations. J. Mol. Graph. Model. 25, 247\u2013260 (2006).","journal-title":"J. Mol. Graph. Model."},{"key":"96226_CR56","doi-asserted-by":"publisher","first-page":"2384","DOI":"10.1063\/1.439486","volume":"72","author":"HC Andersen","year":"1980","unstructured":"Andersen, H. C. Molecular dynamics simulations at constant pressure and\/or temperature. The J. Chem. Phys. 72, 2384\u20132393 (1980).","journal-title":"The J. Chem. Phys."},{"key":"96226_CR57","doi-asserted-by":"publisher","first-page":"8577","DOI":"10.1063\/1.470117","volume":"103","author":"U Essmann","year":"1995","unstructured":"Essmann, U. et al. A smooth particle mesh Ewald method. J. Chem. Phys. 103, 8577\u20138593 (1995).","journal-title":"J. Chem. Phys."},{"key":"96226_CR58","doi-asserted-by":"publisher","first-page":"3696","DOI":"10.1021\/acs.jctc.5b00255","volume":"11","author":"JA Maier","year":"2015","unstructured":"Maier, J. A. et al. ff14SB: Improving the accuracy of protein side chain and backbone parameters from ff99SB. J. Chem. Theory Comput. 11, 3696\u20133713 (2015).","journal-title":"J. Chem. Theory Comput."},{"key":"96226_CR59","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1517\/17460441.2015.1032936","volume":"10","author":"S Genheden","year":"2015","unstructured":"Genheden, S. & Ryde, U. The MM\/PBSA and MM\/GBSA methods to estimate ligand-binding affinities. Expert Opin. Drug Discov. 10, 449\u2013461 (2015).","journal-title":"Expert Opin. Drug Discov."},{"key":"96226_CR60","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1002\/jcc.20084","volume":"25","author":"EF Pettersen","year":"2004","unstructured":"Pettersen, E. F. et al. UCSF Chimera\u2014A visualization system for exploratory research and analysis. J. Comput. Chem. 25, 1605\u20131612 (2004).","journal-title":"J. Comput. Chem."},{"key":"96226_CR61","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/0263-7855(96)00018-5","volume":"14","author":"W Humphrey","year":"1996","unstructured":"Humphrey, W., Dalke, A. & Schulten, K. V. M. D. Visual molecular dynamics. J. Mol. Graph. 14, 33\u201338 (1996).","journal-title":"J. Mol. Graph."},{"key":"96226_CR62","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1021\/ar00109a003","volume":"18","author":"RF Bader","year":"1985","unstructured":"Bader, R. F. Atoms in molecules. Acc. Chem. Res. 18, 9\u201315 (1985).","journal-title":"Acc. Chem. Res."},{"key":"96226_CR63","doi-asserted-by":"publisher","first-page":"580","DOI":"10.1002\/jcc.22885","volume":"33","author":"T Lu","year":"2012","unstructured":"Lu, T. & Chen, F. Multiwfn: a multifunctional wavefunction analyzer. J. Comput. Chem. 33, 580\u2013592 (2012).","journal-title":"J. Comput. Chem."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-96226-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-96226-6","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-96226-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,7]],"date-time":"2023-11-07T10:29:09Z","timestamp":1699352949000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-96226-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,19]]},"references-count":63,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["96226"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-96226-6","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-451061\/v1","asserted-by":"object"}]},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,19]]},"assertion":[{"value":"22 April 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 August 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 August 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"16856"}}