{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T22:46:07Z","timestamp":1792190767414,"version":"4.4.0"},"reference-count":153,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,2,7]],"date-time":"2021-02-07T00:00:00Z","timestamp":1612656000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>In the 21st century and especially during a pandemic, the diagnosis and treatment of depression is an essential part of the daily practice of many family doctors. It mainly affects patients in the age category 15\u201344 years, regardless of gender. Anxiety disorders are often diagnosed in children and adolescents. Social phobias can account for up to 13% of these diagnoses. Social anxiety manifests itself in fear of negative social assessment and humiliation, which disrupts the quality of social functioning. Treatment of the above-mentioned disorders is based on psychotherapy and pharmacotherapy. Serious side effects or mortality from antidepressant drug overdose are currently rare. Recent studies indicate that paroxetine (ATC code: N06AB), belonging to the selective serotonin reuptake inhibitors, has promising therapeutic effects and is used off-label in children and adolescents. The purpose of this review is to describe the interaction of paroxetine with several molecular targets in various points of view including the basic chemical and pharmaceutical properties. The central point of the review is focused on the pharmacodynamic analysis based on the molecular mechanism of binding paroxetine to various therapeutic targets.<\/jats:p>","DOI":"10.3390\/ijms22041662","type":"journal-article","created":{"date-parts":[[2021,2,8]],"date-time":"2021-02-08T20:51:51Z","timestamp":1612817511000},"page":"1662","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":71,"title":["Paroxetine\u2014Overview of the Molecular Mechanisms of Action"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7950-5543","authenticated-orcid":false,"given":"Magdalena","family":"Kowalska","sequence":"first","affiliation":[{"name":"Department of Organic Chemistry, Faculty of Pharmacy, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toru\u0144, 2 dr. A. Jurasza St., 85-094 Bydgoszcz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4521-8065","authenticated-orcid":false,"given":"Jacek","family":"Nowaczyk","sequence":"additional","affiliation":[{"name":"Faculty of Chemistry, Nicolaus Copernicus University in Toru\u0144, 7 Gagarina Str., 87-100 Torun, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u0141ukasz","family":"Fija\u0142kowski","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry, Faculty of Pharmacy, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toru\u0144, 2 dr. A. Jurasza St., 85-094 Bydgoszcz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4945-2369","authenticated-orcid":false,"given":"Alicja","family":"Nowaczyk","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry, Faculty of Pharmacy, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toru\u0144, 2 dr. A. Jurasza St., 85-094 Bydgoszcz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,7]]},"reference":[{"key":"ref_1","unstructured":"Gmitrowicz, A., and Janas-Kozik, M. (2018). Zaburzenia Psychiczne Dzieci i M\u0142odzie\u017cy, Medical Tribune Polska."},{"key":"ref_2","unstructured":"Unbound Medicine (2021, January 30). F40\u2013F48\u2014Anxiety, Dissociative, Stress-Related, Somatoform and Other Nonpsychotic Mental Disorders. Available online: https:\/\/www.unboundmedicine.com\/icd\/view\/ICD-10-CM\/934326\/all\/F40_F48___Anxiety__dissociative__stress_related__somatoform_and_other_nonpsychotic_mental_disorders."},{"key":"ref_3","first-page":"66","article-title":"Anxiety Disorders in Children and Adolescents","volume":"40","author":"Rockhill","year":"2010","journal-title":"Curr. Probl. Pediatric Adolesc. Health Care"},{"key":"ref_4","unstructured":"Adaa.org (2021, January 29). Understand the Facts Anxiety and Depression Association of America. Available online: https:\/\/adaa.org\/understanding-anxiety."},{"key":"ref_5","unstructured":"(2021, January 30). Unbound Medicine.F40.11\u2014Social Phobia, Generalized. Available online: https:\/\/www.unboundmedicine.com\/icd\/view\/ICD-10-CM\/943473\/all\/F40_11___Social_phobia_generalized?q=anxiety+disorder+social."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"West, K.B., Wilbanks, J., and Suveg, C. (2020). Exposure Therapy for Separation Anxiety Disorder. Exposure Therapy for Children with Anxiety and OCD: Clinician\u2019s Guide to Integrated Treatment, Academic Press.","DOI":"10.1016\/B978-0-12-815915-6.00007-X"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1016\/j.janxdis.2012.02.014","article-title":"Characterizing the association between parenting and adolescent social phobia","volume":"26","author":"Knappe","year":"2012","journal-title":"J. Anxiety Disord."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1002\/da.22231","article-title":"Social anxiety disorder in DSM-5. Depression and Anxiety","volume":"31","author":"Heimberg","year":"2014","journal-title":"Depress. Anxiety"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.acap.2008.11.010","article-title":"Off-label prescribing to children in the United States outpatient setting","volume":"9","author":"Bazzano","year":"2009","journal-title":"Acad. Pediatrics"},{"key":"ref_10","unstructured":"ATC Code (2021, January 30). Anatomical Therapeutic Chemical Classification System. Available online: http:\/\/www.atccode.com\/."},{"key":"ref_11","unstructured":"DrugBank (2021, January 30). Paroxetine. Available online: https:\/\/go.drugbank.com\/drugs\/DB00715."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/j.matpr.2020.01.568","article-title":"Paroxetine loaded PLGA nanoparticles","volume":"28","author":"Sharma","year":"2020","journal-title":"Mater. Today Proc."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1517\/14656566.9.5.787","article-title":"Paroxetine","volume":"9","author":"Tang","year":"2008","journal-title":"Expert Opin. Pharmacother."},{"key":"ref_14","first-page":"498","article-title":"Off-label applications for SSRIs","volume":"68","author":"Stone","year":"2003","journal-title":"Am. Fam. Physician"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"172732","DOI":"10.1016\/j.ejphar.2019.172732","article-title":"Off-label uses of drugs for depression","volume":"865","year":"2019","journal-title":"Eur. J. Pharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2778","DOI":"10.1021\/ci200227u","article-title":"LigPlot+: Multiple ligand\u2013Protein interaction diagrams for drug discovery","volume":"51","author":"Laskowski","year":"2011","journal-title":"J. Chem. Inf. Model."},{"key":"ref_17","unstructured":"Unbound Medicine (2021, January 30). F41.1\u2014Generalized Anxiety Disorder. Available online: https:\/\/www.unboundmedicine.com\/icd\/view\/ICD-10-CM\/905183\/all\/F41_1___Generalized_anxiety_disorder?q=300.02."},{"key":"ref_18","unstructured":"Unbound Medicine (2021, January 30). 300.3\u2014Obsessive-Compulsive Disorders. Available online: https:\/\/www.unboundmedicine.com\/icd\/\/search?st=OSS&q=300.3."},{"key":"ref_19","unstructured":"Unbound Medicine (2021, January 30). F33\u2014Major Depressive Disorder, Recurrent. Available online: https:\/\/www.unboundmedicine.com\/icd\/view\/ICD-10-CM\/930155\/all\/F33___Major_depressive_disorder_recurrent?q=depressive+disorder+major."},{"key":"ref_20","unstructured":"Unbound Medicine (2021, January 30). F32.81\u2014Premenstrual Dysphoric Disorder. Available online: https:\/\/www.unboundmedicine.com\/icd\/view\/ICD-10-CM\/968287\/all\/F32_81___Premenstrual_dysphoric_disorder?q=disorder+dysphoric+premenstrual."},{"key":"ref_21","unstructured":"Unbound Medicine (2021, January 30). F43.1\u2014Post-Traumatic Stress Disorder (PTSD). Available online: https:\/\/www.unboundmedicine.com\/icd\/view\/ICD-10-CM\/929135\/all\/F43_1___Post_traumatic_stress_disorder__PTSD_?q=f43.1."},{"key":"ref_22","unstructured":"Unbound Medicine (2021, January 30). F41.0\u2014Panic Disorder [Episodic Paroxysmal Anxiety]. Available online: https:\/\/www.unboundmedicine.com\/icd\/view\/ICD-10-CM\/915404\/all\/F41_0___Panic_disorder_[episodic_paroxysmal_anxiety]?q=anxiety+disorder+generalized."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e11547","DOI":"10.1097\/MD.0000000000011547","article-title":"Efficacy and tolerability of fluvoxamine in adults with social anxiety disorder: A meta-analysis","volume":"97","author":"Liu","year":"2018","journal-title":"Medicine"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"77","DOI":"10.3109\/13651501.2012.667114","article-title":"Guidelines for the pharmacological treatment of anxiety disorders, obsessive\u2013compulsive disorder and posttraumatic stress disorder in primary care","volume":"16","author":"Bandelow","year":"2012","journal-title":"Int. J. Psychiatry Clin. Pract."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1177\/0269881105059253","article-title":"Evidence-based guidelines for the pharmacological treatment of anxiety disorders: Recommendations from the British Association for Psychopharmacology","volume":"19","author":"Baldwin","year":"2005","journal-title":"J. Psychopharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1097\/00004714-199602000-00002","article-title":"Paroxetine as a treatment for premenstrual dysphoric disorder","volume":"16","author":"Yonkers","year":"1996","journal-title":"J. Clin. Psychopharmacol."},{"key":"ref_27","first-page":"242","article-title":"Successful Suicide in a Child: Depression-Related or ParoxetineInduced?","volume":"6","author":"Aghakhani","year":"2016","journal-title":"Int. J. Med Toxicol. Forensic Med."},{"key":"ref_28","unstructured":"Lenox, R.H., and Frazer, A. (2010). Neuropsychopharmacology: The Fifth Generation of Progress, Lippincott Williams and Wilkins."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1542\/peds.2009-2317","article-title":"Comparative safety of antidepressant agents for children and adolescents regarding suicidal acts","volume":"125","author":"Schneeweiss","year":"2010","journal-title":"Pediatrics"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1176\/ajp.147.2.207","article-title":"Emergence of intense suicidal preoccupation during fluoxetine treatment","volume":"147","author":"Teicher","year":"1990","journal-title":"Am. J. Psychiatry"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Hetrick, S.E., McKenzie, J.E., Cox, G.R., Simmons, M.B., and Merry, S.N. (2012). Newer generation antidepressants for depressive disorders in children and adolescents. Cochrane Database Syst. Rev.","DOI":"10.1002\/14651858.CD004851.pub3"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"47","DOI":"10.3109\/13651501.2015.1117111","article-title":"Antidepressants and, suicide and self-injury: Causal or casual association?","volume":"20","author":"Pozzi","year":"2016","journal-title":"Int. J. Psychiatry Clin. Pract."},{"key":"ref_33","first-page":"247","article-title":"Adolescent angst or true intent? Suicidal behavior, risk, and neurobiological mechanisms in depressed children and teenagers taking antidepressants","volume":"16","author":"Morrison","year":"2014","journal-title":"Int. J. Emerg. Ment. Health"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1515\/IJAMH.2005.17.3.211","article-title":"Selective serotonin reuptake inhibitors and the risk for suicidality in adolescents: An update","volume":"17","author":"Giner","year":"2005","journal-title":"Int. J. Adolesc. Med. Health"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1744","DOI":"10.2105\/AJPH.2005.066951","article-title":"US suicide rates by age group, 1970\u20132002: An examination of recent trends","volume":"96","author":"McKeown","year":"2006","journal-title":"Am. J. Public Health"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/S0013-7006(05)82395-4","article-title":"Selective serotonin reuptake inhibitors in major depressive disorder in children and adolescents (ratio of benefits\/risks)","volume":"31","author":"Hjalmarsson","year":"2005","journal-title":"Encephale"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1001\/archpsyc.63.3.332","article-title":"Suicidality in pediatric patients treated with antidepressant drugs","volume":"63","author":"Hammad","year":"2006","journal-title":"Arch. Gen. Psychiatry"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Termorshuizen, F., Palmen, S.J., and Heerdink, E.R. (2016). Suicide behavior before and after the start with antidepressants: A high persistent risk in the first month of treatment among the young. Int. J. Neuropsychopharmacol., 19.","DOI":"10.1093\/ijnp\/pyv081"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"i545","DOI":"10.1136\/bmj.i545","article-title":"Antidepressants may double risk of suicide and aggression in children, study finds","volume":"352","author":"Wise","year":"2016","journal-title":"BMJ"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1111\/j.1600-0447.2007.01003.x","article-title":"The treatment of child and adolescent depression: A matter of concern?","volume":"115","author":"Thomsen","year":"2007","journal-title":"Acta Psychiatr. Scand."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e19573","DOI":"10.1097\/MD.0000000000019573","article-title":"Efficacy and tolerability of paroxetine in adults with social anxiety disorder: A meta-analysis of randomized controlled trials","volume":"99","author":"Li","year":"2020","journal-title":"Medicine"},{"key":"ref_42","first-page":"77","article-title":"Paroxetine\u2014the antidepressant from hell? Probably not, but caution required","volume":"46","author":"Nevels","year":"2016","journal-title":"Psychopharmacol. Bull."},{"key":"ref_43","first-page":"367","article-title":"Paroxetine Hydrochloride. Profiles of Drug Substances","volume":"38","author":"Germann","year":"2013","journal-title":"Excip. Relat. Methodol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.1093\/chromsci\/bmt200","article-title":"Determination of paroxetine in blood and urine using micellar liquid chromatography with electrochemical detection","volume":"52","author":"Agrawal","year":"2014","journal-title":"J. Chromatogr. Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1586\/14737175.7.2.107","article-title":"Paroxetine: Current status in psychiatry","volume":"7","author":"Pae","year":"2007","journal-title":"Expert Rev. Neurother."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1185\/030079902125001353","article-title":"Focus on paroxetine","volume":"19","author":"Green","year":"2003","journal-title":"Curr. Med Res. Opin."},{"key":"ref_47","unstructured":"GlaxoSmithKline (2021, January 30). PAXIL (Paroxetine Hydrochloride) Tablets and Oral Suspension: Prescribing Information. Available online: https:\/\/www.baumhedlundlaw.com\/documents\/pdf\/dolin-trial-exhibits\/JX-3-2007-Paxil-label-prescribing-information.pdf."},{"key":"ref_48","unstructured":"GSK Canada (2014). PAXIL\u2014Product monograph. Compend. Pharm. Specialties. Ott. Can. Pharm. Assoc., 1, 1255\u20131260."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Patetsos, E., and Horjales-Araujo, E. (2016). Treating Chronic Pain with SSRIs: What Do We Know?. Pain Res. Manag.","DOI":"10.1155\/2016\/2020915"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1124\/jpet.115.223768","article-title":"Altering Metabolic Profiles of Drugs by Precision Deuteration: Reducing Mechanism-Based Inhibition of CYP2D6 by Paroxetines","volume":"354","author":"Uttamsingh","year":"2015","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Ogata, N., de Souza Dantas, L.M., and Crowell-Davis, S.L. (2019). Selective serotonin reuptake inhibitors. Vet. Psychopharmacol., 103\u2013128.","DOI":"10.1002\/9781119226253.ch8"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1038\/nature17629","article-title":"X-ray structures and mechanism of the human serotonin transporter","volume":"532","author":"Coleman","year":"2016","journal-title":"Nature"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1038\/s41594-018-0026-8","article-title":"Structural basis for recognition of diverse antidepressants by the human serotonin transporter","volume":"25","author":"Coleman","year":"2018","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"e56427","DOI":"10.7554\/eLife.56427","article-title":"Chemical and structural investigation of the paroxetine-human serotonin transporter complex","volume":"9","author":"Coleman","year":"2020","journal-title":"eLife"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1124\/jpet.113.204776","article-title":"A structural snapshot of CYP2B4 in complex with paroxetine provides insights into ligand binding and clusters of conformational states","volume":"346","author":"Shah","year":"2013","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1124\/mol.113.089631","article-title":"Structural and functional analysis of G protein\u2013coupled receptor kinase inhibition by paroxetine and a rationally designed analog","volume":"85","author":"Homan","year":"2014","journal-title":"Mol. Pharmacol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1830","DOI":"10.1021\/cb3003013","article-title":"Paroxetine is a direct inhibitor of g protein-coupled receptor kinase 2 and increases myocardial contractility","volume":"7","author":"Thal","year":"2012","journal-title":"ACS Chem. Biol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1038\/nature12648","article-title":"Structural basis for action by diverse antidepressants on biogenic amine transporters","volume":"503","author":"Wang","year":"2013","journal-title":"Nature"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1021\/acs.jmedchem.7b01249","article-title":"Target identification and mode of action of four chemically divergent drugs against Ebolavirus infection","volume":"61","author":"Ren","year":"2018","journal-title":"J. Med. Chem."},{"key":"ref_60","unstructured":"GlobalData UK Ltd (2021, January 30). Post-Traumatic Stress Disorder (PTSD)\u2014Opportunity Analysis and Forecasts to 2028. Available online: https:\/\/store.globaldata.com\/report\/gdhc095poa--post-traumatic-stress-disorder-ptsd-opportunity-analysis-and-forecasts-to-2028\/?utm_source=pharma&utm_medium=Research%20Reports&utm_campaign=RSReportPage?utm_source=pharma&utm_campaign=RShomepage."},{"key":"ref_61","unstructured":"PubChem (2021, January 30). Paroxetine, Available online: https:\/\/pubchem.ncbi.nlm.nih.gov\/compound\/43815."},{"key":"ref_62","unstructured":"CCDC (2021, January 30). Access Structures. Available online: https:\/\/www.ccdc.cam.ac.uk\/structures\/."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"3515","DOI":"10.1021\/mp3003573","article-title":"Identification and characterization of stoichiometric and nonstoichiometric hydrate forms of paroxetine HCl: Reversible changes in crystal dimensions as a function of water absorption","volume":"9","author":"Pina","year":"2012","journal-title":"Mol. Pharm."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1731","DOI":"10.1246\/bcsj.72.1731","article-title":"Structure analyses of two crystal forms of paroxetine hydrochloride","volume":"72","author":"Yokota","year":"1999","journal-title":"Bull. Chem. Soc. Jpn."},{"key":"ref_65","unstructured":"SpectraBase (2021, January 30). Paroxetine. Available online: https:\/\/spectrabase.com\/spectrum\/3GQhXHaQFxC."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1002\/mrc.1642","article-title":"Quantitative 1H NMR method for the routine spectroscopic determination of enantiomeric purity of active pharmaceutical ingredients fenfluramine, sertraline, and paroxetine","volume":"43","author":"Salsbury","year":"2005","journal-title":"Magn. Reson. Chem."},{"key":"ref_67","unstructured":"MassBank of North America (MoNA) (2021, January 30). Spectrum AU152606 for Paroxetine. Available online: https:\/\/mona.fiehnlab.ucdavis.edu\/spectra\/display\/AU152606."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1016\/j.cca.2018.10.043","article-title":"The right blood collection tube for therapeutic drug monitoring and toxicology screening procedures: Standard tubes, gel or mechanical separator?","volume":"488","author":"Schrapp","year":"2018","journal-title":"Clin. Chim. Acta"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1111\/j.1600-0447.1989.tb07176.x","article-title":"A review of the metabolism and pharmacokinetics of paroxetine in man","volume":"80","author":"Kaye","year":"1989","journal-title":"Acta Psychiatr. Scand."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/srep23789","article-title":"Mechanism of Paroxetine (Paxil) Inhibition of the Serotonin Transporter","volume":"6","author":"Davis","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"D608","DOI":"10.1093\/nar\/gkx1089","article-title":"HMDB 4.0: The human metabolome database for 2018","volume":"46","author":"Wishart","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_72","unstructured":"HMDB (2021, January 30). Showing Metabocard for Paroxetine (HMDB0014853). Available online: https:\/\/hmdb.ca\/metabolites\/HMDB0014853#identification."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/nar\/28.1.27","article-title":"KEGG: Kyoto encyclopedia of genes and genomes","volume":"28","author":"Kanehisa","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref_74","unstructured":"KEGG (2021, January 30). DRUG: Paroxetine. Available online: https:\/\/www.kegg.jp\/dbget-bin\/www_bget?dr:D02362."},{"key":"ref_75","unstructured":"(2021, January 30). Human Cytochrome P450s. Available online: https:\/\/drnelson.uthsc.edu\/human.P450.table.html."},{"key":"ref_76","unstructured":"Channels, D.B. (2021, January 30). Available online: https:\/\/webchemdev.ncbr.muni.cz\/ChannelsDB\/."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.pharmthera.2012.12.007","article-title":"Cytochrome P450 enzymes in drug metabolism: Regulation of gene expression, enzyme activities, and impact of genetic variation","volume":"138","author":"Zanger","year":"2013","journal-title":"Pharmacol. Ther."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.1080\/004982598238886","article-title":"Inhibition and induction of human cytochrome P450 (CYP) enzymes","volume":"28","author":"Pelkonen","year":"1998","journal-title":"Xenobiotica"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"361","DOI":"10.2165\/00003088-199835050-00003","article-title":"Inhibition and induction of cytochrome P450 and the clinical implications","volume":"35","author":"Lin","year":"1998","journal-title":"Clin. Pharmacokinet."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1111\/j.1600-0447.1989.tb07163.x","article-title":"Metabolic pathway of paroxetine in animals and man and the comparative pharmacological properties of its metabolites","volume":"80","author":"Haddock","year":"1989","journal-title":"Acta Psychiatr. Scand."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1111\/j.1527-3458.2001.tb00189.x","article-title":"Paroxetine: A review","volume":"7","author":"Bourin","year":"2001","journal-title":"Cns Drug Rev."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Taylor, C., Crosby, I., Yip, V., Maguire, P., Pirmohamed, M., and Turner, R.M. (2020). A Review of the Important Role of CYP2D6 in Pharmacogenomics. Genes, 11.","DOI":"10.3390\/genes11111295"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1451","DOI":"10.4155\/fmc.10.229","article-title":"Structural features of cytochromes P450 and ligands that affect drug metabolism as revealed by X-ray crystallography and NMR","volume":"2","author":"Gay","year":"2010","journal-title":"Future Med. Chem."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Urban, P., Lautier, T., Pompon, D., and Truan, G. (2018). Ligand access channels in cytochrome P450 enzymes: A review. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19061617"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1023\/A:1015920931701","article-title":"Cytochrome P450: Molecular architecture, mechanism, and prospects for rational inhibitor design","volume":"5","author":"Poulos","year":"1988","journal-title":"Pharm. Res."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1007\/s00775-016-1430-3","article-title":"A new look at the role of thiolate ligation in cytochrome P450","volume":"22","author":"Yosca","year":"2017","journal-title":"Jbic J. Biol. Inorg. Chem."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1039\/b101297p","article-title":"Oxidizing species in the mechanism of cytochrome P450","volume":"19","year":"2002","journal-title":"Nat. Prod. Rep."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"3334","DOI":"10.1039\/D0OB00529K","article-title":"The quasi-irreversible inactivation of cytochrome P450 enzymes by paroxetine: A computational approach","volume":"18","author":"Kamel","year":"2020","journal-title":"Org. Biomol. Chem."},{"key":"ref_89","first-page":"185","article-title":"Cytochrome P450 2B6: Function, genetics, and clinical relevance","volume":"27","author":"Turpeinen","year":"2012","journal-title":"Drug Metab. Pers. Ther."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"598","DOI":"10.2174\/138920008785821710","article-title":"CYP2B6: New insights into a historically overlooked cytochrome P450 isozyme","volume":"9","author":"Wang","year":"2008","journal-title":"Curr. Drug Metab."},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Correia, M.A., and de Montellano, P.R.O. (2005). Inhibition of cytochrome P450 enzymes. Cytochrome P450, Springer.","DOI":"10.1007\/b139087"},{"key":"ref_92","unstructured":"Stahl, S.M. (2000). Essential Psychopharmacology: Neuroscientific Basis and Practical Applications, Cambridge University Press."},{"key":"ref_93","first-page":"705","article-title":"Evaluation of 227 Drugs for In Vitro Inhibition of Cytochrome P450 2B6","volume":"7","author":"Walsky","year":"2006","journal-title":"Drug Metab."},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Cho, Y.-W., Kim, E.-J., Nyiramana, M.M., Shin, E.-J., Jin, H., Ryu, J.H., Kang, K.R., Lee, G.-W., Kim, H.J., and Han, J. (2019). Paroxetine induces apoptosis of human breast cancer mcf-7 cells through Ca2+-and p38 map kinase-dependent ros generation. Cancers, 11.","DOI":"10.3390\/cancers11010064"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1093\/toxsci\/kfv141","article-title":"Cell-based high-throughput screening for aromatase inhibitors in the Tox21 10K library","volume":"147","author":"Chen","year":"2015","journal-title":"Toxicol. Sci."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1093\/toxsci\/kfu023","article-title":"AroER tri-screen is a biologically relevant assay for endocrine disrupting chemicals modulating the activity of aromatase and\/or the estrogen receptor","volume":"139","author":"Chen","year":"2014","journal-title":"Toxicol. Sci."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"7614","DOI":"10.1074\/jbc.M511232200","article-title":"Crystal structure of human cytochrome P450 2D6","volume":"281","author":"Rowland","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"705","DOI":"10.2174\/138920006778520633","article-title":"The functional role of CYP2B6 in human drug metabolism: Substrates and inhibitors in vitro, in vivo and in silico","volume":"7","author":"Turpeinen","year":"2006","journal-title":"Curr. Drug Metab."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"310","DOI":"10.2174\/138920008784220664","article-title":"Drugs behave as substrates, inhibitors and inducers of human cytochrome P450 3A4","volume":"9","author":"Zhou","year":"2008","journal-title":"Curr. Drug Metab."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"167","DOI":"10.2174\/138920012798918417","article-title":"Plasticity of CYP2B enzymes: Structural and solution biophysical methods","volume":"13","author":"Wilderman","year":"2012","journal-title":"Curr. Drug Metab."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1007\/s00894-009-0478-1","article-title":"Structure and localisation of drug binding sites on neurotransmitter transporters","volume":"15","author":"Ravna","year":"2009","journal-title":"J. Mol. Modeling"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.sbi.2019.03.011","article-title":"Insights into the mechanism and pharmacology of neurotransmitter sodium symporters","volume":"54","author":"Navratna","year":"2019","journal-title":"Curr. Opin. Struct. Biol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1038\/nature03978","article-title":"Crystal structure of a bacterial homologue of Na+\/Cl\u2212-dependent neurotransmitter transporters","volume":"437","author":"Yamashita","year":"2005","journal-title":"Nature"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"15650","DOI":"10.1038\/srep15650","article-title":"Binding site residues control inhibitor selectivity in the human norepinephrine transporter but not in the human dopamine transporter","volume":"5","author":"Andersen","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"C196","DOI":"10.1152\/ajpcell.1990.259.2.C196","article-title":"High-affinity paroxetine binding to the human placental serotonin transporter","volume":"259","author":"Cool","year":"1990","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/S0014-2999(97)01393-9","article-title":"Pharmacological profile of antidepressants and related compounds at human monoamine transporters","volume":"340","author":"Tatsumi","year":"1997","journal-title":"Eur. J. Pharmacol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1278","DOI":"10.1001\/archpsyc.1981.01780360094011","article-title":"Effects of Clonidine on Anxiety Disorders","volume":"38","author":"Merchant","year":"1981","journal-title":"Arch. Gen. Psychiatry"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1300","DOI":"10.1017\/S1047951119001938","article-title":"Severe transient neonatal long QT syndrome due to maternal paroxetine usage: A case report","volume":"29","author":"Leerssen","year":"2019","journal-title":"Cardiol. Young"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1208\/s12248-017-0155-8","article-title":"Real Patient and its Virtual Twin: Application of Quantitative Systems Toxicology Modelling in the Cardiac Safety Assessment of Citalopram","volume":"20","author":"Patel","year":"2018","journal-title":"Aaps J."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"2558","DOI":"10.1021\/acschembio.7b00338","article-title":"Mapping the binding site for escitalopram and paroxetine in the human serotonin transporter using genetically encoded photo-cross-linkers","volume":"12","author":"Rannversson","year":"2017","journal-title":"ACS Chem. Biol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1038\/nature12533","article-title":"X-ray structure of dopamine transporter elucidates antidepressant mechanism","volume":"503","author":"Penmatsa","year":"2013","journal-title":"Nature"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"43694","DOI":"10.1074\/jbc.M112.342212","article-title":"Interaction of Antidepressants with the Serotonin and Norepinephrine Transporters mutational studies of the S1 substrate binding pocket","volume":"287","author":"Andersen","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"107411","DOI":"10.1016\/j.neuropharm.2018.10.040","article-title":"Computation-guided analysis of paroxetine binding to hSERT reveals functionally important structural elements and dynamics","volume":"161","author":"Abramyan","year":"2019","journal-title":"Neuropharmacology"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"755","DOI":"10.2174\/156802609789207091","article-title":"Docking screens: Right for the right reasons?","volume":"9","author":"Kolb","year":"2009","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1038\/nrd.2017.178","article-title":"Trends in GPCR drug discovery: New agents, targets and indications","volume":"16","author":"Hauser","year":"2017","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1124\/mol.117.111062","article-title":"G protein-coupled receptors as targets for approved drugs: How many targets and how many drugs?","volume":"93","author":"Sriram","year":"2018","journal-title":"Mol. Pharmacol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1007\/s00109-009-0450-7","article-title":"GRK mythology: G-protein receptor kinases in cardiovascular disease","volume":"87","author":"Dorn","year":"2009","journal-title":"J. Mol. Med."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1124\/mol.111.071522","article-title":"Molecular mechanism of selectivity among G protein-coupled receptor kinase 2 inhibitors","volume":"80","author":"Thal","year":"2011","journal-title":"Mol. Pharmacol."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1080\/14728222.2018.1406925","article-title":"GRK2 as a therapeutic target for heart failure","volume":"22","author":"Cannavo","year":"2018","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-019-48949-w","article-title":"Computational study of paroxetine-like inhibitors reveals new molecular insight to inhibit GRK2 with selectivity over ROCK1","volume":"9","author":"Keretsu","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1006\/jmcc.2001.1358","article-title":"Altered beta-adrenergic receptor gene regulation and signaling in chronic heart failure","volume":"33","author":"Port","year":"2001","journal-title":"J. Mol. Cell Cardiol."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"204","DOI":"10.4330\/wjc.v7.i4.204","article-title":"Autonomic and endocrine control of cardiovascular function","volume":"7","author":"Gordan","year":"2015","journal-title":"World J. Cardiol."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1161\/01.CIR.37.2.279","article-title":"Some aspects of the biological role of adenosine 3\u2019,5\u2019-monophosphate (cyclic AMP)","volume":"37","author":"Sutherland","year":"1968","journal-title":"Circulation"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1038\/415206a","article-title":"Seven-transmembrane-spanning receptors and heart function","volume":"415","author":"Rockman","year":"2002","journal-title":"Nature"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.phrs.2016.05.008","article-title":"The expanding GRK interactome: Implications in cardiovascular disease and potential for therapeutic development","volume":"110","author":"Hullmann","year":"2016","journal-title":"Pharmacol. Res."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1038\/nm1553","article-title":"Adrenal GRK2 upregulation mediates sympathetic overdrive in heart failure","volume":"13","author":"Lymperopoulos","year":"2007","journal-title":"Nat. Med."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"3052","DOI":"10.1021\/acs.jmedchem.7b00112","article-title":"Structure-based design of highly selective and potent G protein-coupled receptor kinase 2 inhibitors based on paroxetine","volume":"60","author":"Waldschmidt","year":"2017","journal-title":"J. Med. Chem."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1161\/CIRCRESAHA.107.168336","article-title":"G protein\u2013coupled receptor kinase 2 ablation in cardiac myocytes before or after myocardial infarction prevents heart failure","volume":"103","author":"Raake","year":"2008","journal-title":"Circ. Res."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"6958","DOI":"10.1021\/bi050119q","article-title":"The role of G\u03b2\u03b3 and domain interfaces in the activation of G protein-coupled receptor kinase 2","volume":"44","author":"Lodowski","year":"2005","journal-title":"Biochemistry"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"112","DOI":"10.3389\/fphar.2019.00112","article-title":"G protein-coupled receptor kinase 2 (GRK2) as a potential therapeutic target in cardiovascular and metabolic diseases","volume":"10","author":"Murga","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_131","unstructured":"Unbound Medicine (2021, January 30). A98.4\u2014Ebola Virus Disease. Available online: https:\/\/www.unboundmedicine.com\/icd\/view\/ICD-10-CM\/888247\/all\/Ebola%20(virus)."},{"key":"ref_132","unstructured":"World Health Organization (2021, January 30). Ebola Virus Disease. Available online: https:\/\/www.who.int\/en\/news-room\/fact-sheets\/detail\/ebola-virus-disease."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"17","DOI":"10.7774\/cevr.2015.4.1.17","article-title":"Ebola outbreak in Western Africa 2014: What is going on with Ebola virus?","volume":"4","author":"Na","year":"2015","journal-title":"Clin. Exp. Vaccine Res."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"385","DOI":"10.4103\/1995-7645.267581","article-title":"Ebola virus disease: Recent advances in diagnostics and therapeutics","volume":"12","author":"Jagga","year":"2019","journal-title":"Asian Pac. J. Trop. Med."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"2699","DOI":"10.1128\/JVI.02344-07","article-title":"Inhibition of IRF-3 activation by VP35 is critical for the high level of virulence of ebola virus","volume":"82","author":"Hartman","year":"2008","journal-title":"J. Virol."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"55750","DOI":"10.18632\/oncotarget.18498","article-title":"The lifecycle of the Ebola virus in host cells","volume":"8","author":"Yu","year":"2017","journal-title":"Oncotarget"},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1038\/nature18615","article-title":"Toremifene interacts with and destabilizes the Ebola virus glycoprotein","volume":"535","author":"Zhao","year":"2016","journal-title":"Nature"},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"1841","DOI":"10.1016\/j.celrep.2019.01.065","article-title":"Release of immunomodulatory Ebola virus glycoprotein-containing microvesicles is suppressed by tetherin in a species-specific manner","volume":"26","author":"Nehls","year":"2019","journal-title":"Cell Rep."},{"key":"ref_139","doi-asserted-by":"crossref","unstructured":"Rooney, A., and Grant, R. (2010). Pharmacological treatment of depression in patients with a primary brain tumour. Cochrane Database Syst. Rev.","DOI":"10.1002\/14651858.CD006932.pub2"},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1111\/jcmm.14011","article-title":"Anticancer activity of paroxetine in human colon cancer cells: Involvement of MET and ERBB3","volume":"23","author":"Jang","year":"2019","journal-title":"J. Cell Mol. Med."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"1571","DOI":"10.1002\/ehf2.12706","article-title":"Pharmacological inhibition of GRK2 improves cardiac metabolism and function in experimental heart failure","volume":"7","author":"Ciccarelli","year":"2020","journal-title":"ESC Heart Fail."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00894-020-04444-y","article-title":"Inverse in silico\u2013in vitro fishing of unexpected paroxetine kinase targets from tumor druggable kinome","volume":"26","author":"Zhou","year":"2020","journal-title":"J. Mol. Modeling"},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"5495","DOI":"10.2147\/OTT.S112242","article-title":"Sunitinib: The antiangiogenic effects and beyond","volume":"9","author":"Hao","year":"2016","journal-title":"Oncotargets Ther."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1038\/nrd2380","article-title":"Molecular basis for sunitinib efficacy and future clinical development","volume":"6","author":"Faivre","year":"2007","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"1487","DOI":"10.1016\/j.jaad.2020.05.104","article-title":"Tofacitinib in the treatment of lichen planopilaris: A retrospective review","volume":"83","author":"Plante","year":"2020","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_146","unstructured":"FDA (2021, January 30). Drug Approval Package, Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/99\/20-936_Paxil.cfm."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"884","DOI":"10.1200\/JCO.2006.06.3602","article-title":"Sunitinib: From rational design to clinical efficacy","volume":"25","author":"Chow","year":"2007","journal-title":"J. Clin. Oncol."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13058-020-01346-y","article-title":"Sunitinib facilitates metastatic breast cancer spreading by inducing endothelial cell senescence","volume":"22","author":"Wang","year":"2020","journal-title":"Breast Cancer Res."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"1074","DOI":"10.1016\/j.clinthera.2014.06.018","article-title":"Systematic review of tofacitinib: A new drug for the management of rheumatoid arthritis","volume":"36","author":"Kaur","year":"2014","journal-title":"Clin. Ther."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"1987","DOI":"10.1007\/s40265-017-0835-9","article-title":"Tofacitinib: A review in rheumatoid arthritis","volume":"77","author":"Dhillon","year":"2017","journal-title":"Drugs"},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12943-018-0801-5","article-title":"Advances in studies of tyrosine kinase inhibitors and their acquired resistance","volume":"17","author":"Jiao","year":"2018","journal-title":"Mol. Cancer"},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"670","DOI":"10.2174\/092986611795445978","article-title":"Gaussian process: A promising approach for the modeling and prediction of peptide binding affinity to MHC proteins","volume":"18","author":"Ren","year":"2011","journal-title":"Protein Pept. Lett."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1208\/s12248-012-9390-1","article-title":"Drug repurposing: Far beyond new targets for old drugs","volume":"14","author":"Oprea","year":"2012","journal-title":"Aaps J."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/4\/1662\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:20:48Z","timestamp":1760160048000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/4\/1662"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,7]]},"references-count":153,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,2]]}},"alternative-id":["ijms22041662"],"URL":"https:\/\/doi.org\/10.3390\/ijms22041662","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,7]]}}}