{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T16:25:28Z","timestamp":1787934328591,"version":"build-2784847793"},"reference-count":60,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2022,7,21]],"date-time":"2022-07-21T00:00:00Z","timestamp":1658361600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Universiti Brunei Darussalam","award":["UBD\/RSCH\/1.6\/FICBF(b)\/2018\/004"],"award-info":[{"award-number":["UBD\/RSCH\/1.6\/FICBF(b)\/2018\/004"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Cytochrome P450 oxidoreductase (POR) is a membrane-bound flavoprotein that helps in transferring electrons from its NADPH domain to all cytochrome P450 (CYP450) enzymes. Mutations in the POR gene could severely affect the metabolism of steroid hormones and the development of skeletal muscles, a condition known as Cytochrome P450 oxidoreductase deficiency (PORD). PORD is associated with clinical presentations of disorders of sex development, Antley and Bixler\u2019s syndrome (ABS), as well as an abnormal steroid hormone profile. We have performed an in silico analysis of POR 3D X-ray protein crystal structure to study the effects of reported mutations on the POR enzyme structure. A total of 32 missense mutations were identified, from 170 PORD patients, and mapped on the 3D crystal structure of the POR enzyme. In addition, five of the missense mutations (R457H, A287P, D210G, Y181D and Y607C) were further selected for an in-depth in silico analysis to correlate the observed changes in POR protein structure with the clinical phenotypes observed in PORD patients. Overall, missense mutations found in the binding sites of POR cofactors could lead to a severe form of PORD, emphasizing the importance of POR cofactor binding domains in transferring electrons to the CYP450 enzyme family.<\/jats:p>","DOI":"10.3390\/molecules27144646","type":"journal-article","created":{"date-parts":[[2022,7,21]],"date-time":"2022-07-21T22:38:50Z","timestamp":1658443130000},"page":"4646","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["In Silico Analysis of PORD Mutations on the 3D Structure of P450 Oxidoreductase"],"prefix":"10.3390","volume":"27","author":[{"given":"Muhammad","family":"Nurhafizuddin","sequence":"first","affiliation":[{"name":"PAPRSB Institute of Health Sciences, Universiti Brunei Darussalam, Jalan Tungku Link, Gadong BE1410, Brunei"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9586-8299","authenticated-orcid":false,"given":"Aziemah","family":"Azizi","sequence":"additional","affiliation":[{"name":"PAPRSB Institute of Health Sciences, Universiti Brunei Darussalam, Jalan Tungku Link, Gadong BE1410, Brunei"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6971-1383","authenticated-orcid":false,"given":"Long Chiau","family":"Ming","sequence":"additional","affiliation":[{"name":"PAPRSB Institute of Health Sciences, Universiti Brunei Darussalam, Jalan Tungku Link, Gadong BE1410, Brunei"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1468-4082","authenticated-orcid":false,"given":"Naeem","family":"Shafqat","sequence":"additional","affiliation":[{"name":"PAPRSB Institute of Health Sciences, Universiti Brunei Darussalam, Jalan Tungku Link, Gadong BE1410, Brunei"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/j.pharmthera.2013.01.010","article-title":"NADPH P450 oxidoreductase: Structure, function, and pathology of diseases","volume":"138","author":"Pandey","year":"2013","journal-title":"Pharmacol. Ther."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.mce.2009.09.001","article-title":"Modeling of human P450 oxidoreductase structure by in silico mutagenesis and MD simulation","volume":"313","author":"Mullis","year":"2009","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1038\/ng1300","article-title":"Mutant P450 oxidoreductase causes disordered steroidogenesis with and without Antley-Bixler syndrome","volume":"36","author":"Tajima","year":"2004","journal-title":"Nat. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"11374","DOI":"10.1074\/jbc.M807868200","article-title":"Structure and Function of an NADPH-Cytochrome P450 Oxidoreductase in an Open Conformation Capable of Reducing Cytochrome P450","volume":"284","author":"Hamdane","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_5","first-page":"63","article-title":"Clinical and Biochemical Consequences of P450 Oxidoreductase Deficiency","volume":"20","author":"Pandey","year":"2010","journal-title":"Endocr. Dev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1016\/S0021-9258(19)70129-X","article-title":"Separate roles for FMN and FAD in catalysis by liver microsomal NADPH-cytochrome P-450 reductase","volume":"256","author":"Vermilion","year":"1981","journal-title":"J. Biol. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2297","DOI":"10.1021\/bi00736a018","article-title":"Properties of Hepatic Reduced Nicotinamide Adenine Dinucleotide Phosphate-Cytochrome C Reductase","volume":"12","author":"Iyanagi","year":"1973","journal-title":"Biochemistry"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1159\/000114857","article-title":"Genetic and Clinical Features of P450 Oxidoreductase Deficiency","volume":"69","author":"Scott","year":"2008","journal-title":"Horm. Res. Paediatr."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1182","DOI":"10.1056\/NEJM198511073131903","article-title":"Male pseudohermaphroditism due to multiple defects in steroid-biosynthetic microsomal mixed-function oxidases. A new variant of congenital adrenal hyperplasia","volume":"313","author":"Peterson","year":"1985","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1056\/NEJM198711263172211","article-title":"Congenital adrenal hyperplasia","volume":"317","author":"Miller","year":"1987","journal-title":"N. Engl. J. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"6536","DOI":"10.1074\/jbc.M111408200","article-title":"Association of Multiple Developmental Defects and Embryonic Lethality with Loss of Microsomal NADPH-Cytochrome P450 Oxidoreductase","volume":"277","author":"Shen","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"6103","DOI":"10.1128\/MCB.23.17.6103-6116.2003","article-title":"Identification of Novel Roles of the Cytochrome P450 System in Early Embryogenesis: Effects on Vasculogenesis and Retinoic Acid Homeostasis","volume":"23","author":"Otto","year":"2003","journal-title":"Mol. Cell. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"E257","DOI":"10.1210\/jc.2011-0640","article-title":"Genotype-Phenotype Analysis in Congenital Adrenal Hyperplasia due to P450 Oxidoreductase Deficiency","volume":"97","author":"Krone","year":"2012","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1186\/s13023-019-1283-2","article-title":"Novel phenotypes and genotypes in Antley-Bixler syndrome caused by cytochrome P450 oxidoreductase deficiency: Based on the first cohort of Chinese children","volume":"14","author":"Fan","year":"2019","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2128","DOI":"10.1016\/S0140-6736(04)16503-3","article-title":"Congenital adrenal hyperplasia caused by mutant P450 oxidoreductase and human androgen synthesis: Analytical study","volume":"363","author":"Arlt","year":"2004","journal-title":"Lancet"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1002\/ajmg.a.30169","article-title":"Compound heterozygous mutations of cytochrome P450 oxidoreductase gene (POR) in two patients with Antley-Bixler syndrome","volume":"128A","author":"Adachi","year":"2004","journal-title":"Am. J. Med Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1081\/ERC-200044174","article-title":"A Male Twin Infant with Skull Deformity and Elevated Neonatal 17\u2013Hydroxyprogesterone: A Prismatic Case of P450 Oxidoreductase Deficiency","volume":"30","author":"Wudy","year":"2004","journal-title":"Endocr. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1086\/429417","article-title":"Diversity and function of mutations in P450 oxidoreductase in patients with Antley-Bixler syndrome and disordered steroidogenesis","volume":"76","author":"Huang","year":"2005","journal-title":"Am. J. Hum. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1210\/jc.2004-0810","article-title":"Cytochrome P450 Oxidoreductase Gene Mutations and Antley-Bixler Syndrome with Abnormal Genitalia and\/or Impaired Steroidogenesis: Molecular and Clinical Studies in 10 Patients","volume":"90","author":"Fukami","year":"2005","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1203\/01.pdr.0000195825.31504.28","article-title":"Cytochrome P450 Oxidoreductase Deficiency in Three Patients Initially Regarded as Having 21-Hydroxylase Deficiency and\/or Aromatase Deficiency: Diagnostic Value of Urine Steroid Hormone Analysis","volume":"59","author":"Fukami","year":"2006","journal-title":"Pediatr. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2643","DOI":"10.1210\/jc.2005-2460","article-title":"Urine Steroid Hormone Profile Analysis in Cytochrome P450 Oxidoreductase Deficiency: Implication for the Backdoor Pathway to Dihydrotestosterone","volume":"91","author":"Homma","year":"2006","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1797","DOI":"10.1002\/ajmg.a.31385","article-title":"Linking Antley-Bixler syndrome and congenital adrenal hyperplasia: A novel case of P450 oxidoreductase deficiency","volume":"140A","author":"Williamson","year":"2006","journal-title":"Am. J. Med Genet. Part A"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3584","DOI":"10.1210\/jc.2008-0051","article-title":"Homozygous Mutation G539R in the Gene for P450 Oxidoreductase in a Family Previously Diagnosed as Having 17,20-Lyase Deficiency","volume":"93","author":"Hershkovitz","year":"2008","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1007\/s00431-008-0849-0","article-title":"A case of Antley-Bixler syndrome caused by compound heterozygous mutations of the cytochrome P450 oxidoreductase gene","volume":"168","author":"Ko","year":"2009","journal-title":"Eur. J. Pediatr."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1210\/jc.2008-2816","article-title":"Cytochrome P450 oxidoreductase deficiency: Identification and characterization of biallelic mutations and genotype-phenotype correlations in 35 Japanese patients","volume":"94","author":"Fukami","year":"2009","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4992","DOI":"10.1210\/jc.2009-1460","article-title":"Clinical, Genetic, and Enzymatic Characterization of P450 Oxidoreductase Deficiency in Four Patients","volume":"94","author":"Sahakitrungruang","year":"2009","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3418","DOI":"10.1210\/jc.2010-0058","article-title":"Concomitant mutations in the P450 oxidoreductase and androgen receptor genes presenting with 46,XY disordered sex development and androgenization at adrenarche","volume":"95","author":"Idkowiak","year":"2010","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_28","first-page":"59","article-title":"Ambiguous genitalia, impaired steroidogenesis, and Antley-Bixler syndrome in a patient with P450 oxidoreductase deficiency","volume":"16","author":"But","year":"2010","journal-title":"Hong Kong Med. J."},{"key":"ref_29","first-page":"281","article-title":"A rare cause of congenital adrenal hyperplasia: Antley-Bixler syndrome due to POR deficiency","volume":"69","author":"Herkert","year":"2011","journal-title":"Neth. J. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"E453","DOI":"10.1210\/jc.2010-1607","article-title":"Pubertal presentation in seven patients with congenital adrenal hyperplasia due to P450 oxidoreductase deficiency","volume":"96","author":"Idkowiak","year":"2011","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1016\/j.bbrc.2011.08.001","article-title":"Deletion of P399_E401 in NADPH cytochrome P450 oxidoreductase results in partial mixed oxidase deficiency","volume":"412","author":"Mallet","year":"2011","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_32","first-page":"479","article-title":"A case of antley bixler syndrome: Diagnosis and outcome","volume":"8","author":"Puiu","year":"2012","journal-title":"Acta Endocrinol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1590\/S0004-27302012000800020","article-title":"46,XX DSD and Antley-Bixler syndrome due to novel mutations in the cytochrome P450 oxidoreductase gene","volume":"56","author":"Castro","year":"2012","journal-title":"Arq. Bras. Endocrinol. Metabol."},{"key":"ref_34","first-page":"bcr2013010251","article-title":"Disorder of sex development as a diagnostic clue in the first Spanish known newborn with P450 oxidoreductase deficiency","volume":"2013","author":"Albaladejo","year":"2013","journal-title":"BMJ Case Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"E528","DOI":"10.1210\/jc.2012-3449","article-title":"Prenatal Diagnosis of Congenital Adrenal Hyperplasia Caused by P450 Oxidoreductase Deficiency","volume":"98","author":"Reisch","year":"2013","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1159\/000356857","article-title":"Antley-bixler syndrome: Surgical management of ambiguous genitalia\u2014A case report","volume":"23","author":"Boia","year":"2013","journal-title":"Med Princ. Pract."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"882","DOI":"10.12659\/AJCR.895526","article-title":"Prenatal diagnosis of antley-bixler syndrome and POR deficiency","volume":"16","author":"Oldani","year":"2015","journal-title":"Am. J. Case Rep."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"277","DOI":"10.14310\/horm.2002.1679","article-title":"Delayed diagnosis of disorder of sex development (DSD) due to P450 oxidoreductase (POR) deficiency","volume":"15","author":"Koika","year":"2016","journal-title":"Hormones"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4789","DOI":"10.1210\/jc.2016-1928","article-title":"P450 oxidoreductase deficiency: Loss of activity caused by protein instability from a novel L374H mutation","volume":"101","author":"Parween","year":"2016","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1590\/2359-3997000000213","article-title":"Long-term follow-up of a female with congenital adrenal hyperplasia due to P450-oxidoreductase deficiency","volume":"60","author":"Bonamichi","year":"2016","journal-title":"Arch. Endocrinol. Metab."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1002\/bdra.23492","article-title":"Compound heterozygosity of a paternal submicroscopic deletion and a maternal missense mutation inPORgene: Antley-bixler syndrome phenotype in three sibling fetuses","volume":"106","author":"Tzetis","year":"2016","journal-title":"Birth Defects Res. Part A Clin. Mol. Teratol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"902","DOI":"10.12891\/ceog3172.2016","article-title":"P450 oxidoreductase deficiency with maternal virilization during pregnancy","volume":"43","author":"Nakanishi","year":"2016","journal-title":"Clin. Exp. Obstet. Gynecol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"31","DOI":"10.5734\/JGM.2016.13.1.31","article-title":"Two cases of Antley-Bixler syndrome caused by mutations in different genes, FGFR2 and POR","volume":"13","author":"Woo","year":"2016","journal-title":"J. Genet. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/s13048-017-0312-9","article-title":"Cytochrome P450 oxidoreductase deficiency caused by R457H mutation in POR gene in Chinese: Case report and literature review","volume":"10","author":"Bai","year":"2017","journal-title":"J. Ovarian Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"360","DOI":"10.4103\/2230-8210.202031","article-title":"Cytochrome P450 oxidoreductase deficiency: Novel cause of ambiguity with primary amenorrhea","volume":"21","author":"Khadilkar","year":"2017","journal-title":"Indian J. Endocrinol. Metab."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"559","DOI":"10.3343\/alm.2017.37.6.559","article-title":"A Case of Antley-Bixler Syndrome with a Novel Likely Pathogenic Variant (c.529G>C) in the POR Gene","volume":"37","author":"Oh","year":"2017","journal-title":"Ann. Lab. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1080\/09513590.2017.1393663","article-title":"In vitro fertilization-frozen embryo transfer in a patient with cytochrome P450 oxidoreductase deficiency: A case report","volume":"34","author":"Song","year":"2017","journal-title":"Gynecol. Endocrinol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1002\/ped4.12035","article-title":"Compound heterozygous variants in POR gene identified by whole-exome sequencing in a Chinese pedigree with cytochrome P450 oxidoreductase deficiency","volume":"2","author":"Hao","year":"2018","journal-title":"Pediatr. Investig."},{"key":"ref_49","first-page":"1025","article-title":"A case of Antley-Bixler syndrome caused by novel POR mutations","volume":"36","author":"Peng","year":"2019","journal-title":"Zhonghua Yi Xue Yi Chuan Xue Za Zhi"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"97","DOI":"10.6065\/apem.1938152.076","article-title":"Clinical, endocrinological, and molecular features of four Korean cases of cytochrome P450 oxidoreductase deficiency","volume":"25","author":"Lee","year":"2020","journal-title":"Ann. Pediatr. Endocrinol. Metab."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2503","DOI":"10.1007\/s10815-020-01899-z","article-title":"Clinical and genetic analysis of cytochrome P450 oxidoreductase (POR) deficiency in a female and the analysis of a novel POR intron mutation causing alternative mRNA splicing","volume":"37","author":"Zhang","year":"2020","journal-title":"J. Assist. Reprod. Genet."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1007\/s42000-020-00249-z","article-title":"Cytochrome P450 oxidoreductase deficiency caused by a novel mutation in the POR gene in two siblings: Case report and literature review","volume":"20","author":"Unal","year":"2020","journal-title":"Hormones"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"3309","DOI":"10.21037\/tp-21-499","article-title":"Antley-Bixler syndrome arising from compound heterozygotes in the P450 oxidoreductase gene: A case report","volume":"10","author":"Li","year":"2021","journal-title":"Transl. Pediatr."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1111\/cga.12434","article-title":"Two cases of cytochrome P450 oxidoreductase deficiency with severe scoliosis and surgery requirement","volume":"61","author":"Onuki","year":"2021","journal-title":"Congenit. Anom."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1126\/science.181.4096.223","article-title":"Principles that Govern the Folding of Protein Chains","volume":"181","author":"Anfinsen","year":"1973","journal-title":"Science"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1002\/prot.10016","article-title":"Why are proteins marginally stable?","volume":"46","author":"Taverna","year":"2001","journal-title":"Proteins Struct. Funct. Bioinform."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"16152","DOI":"10.1073\/pnas.0705366104","article-title":"Protein stability imposes limits on organism complexity and speed of molecular evolution","volume":"104","author":"Zeldovich","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"103","DOI":"10.3389\/fphar.2014.00103","article-title":"Pharmacogenomics of human P450 oxidoreductase","volume":"5","author":"Pandey","year":"2014","journal-title":"Front. Pharmacol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.jsbmb.2016.03.031","article-title":"Impact on CYP19A1 activity by mutations in NADPH cytochrome P450 oxidoreductase","volume":"165","author":"Pandey","year":"2017","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1733","DOI":"10.1073\/pnas.0711621105","article-title":"Genetics of P450 oxidoreductase: Sequence variation in 842 individuals of four ethnicities and activities of 15 missense mutations","volume":"105","author":"Huang","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/14\/4646\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:55:15Z","timestamp":1760140515000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/14\/4646"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,21]]},"references-count":60,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2022,7]]}},"alternative-id":["molecules27144646"],"URL":"https:\/\/doi.org\/10.3390\/molecules27144646","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,21]]}}}