{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T19:01:40Z","timestamp":1792004500451,"version":"4.4.0"},"reference-count":66,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,1,16]],"date-time":"2025-01-16T00:00:00Z","timestamp":1736985600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,1,16]],"date-time":"2025-01-16T00:00:00Z","timestamp":1736985600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100018777","name":"Nile University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100018777","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Single nucleotide polymorphisms (SNPs) represent the prevailing form of genetic variations observed in the human population. Such variations could alter the encoded enzymes\u2019 activities. CYP3A4\/5 enzymes are involved in metabolizing drugs, notably antivirals against SARS-CoV-2. In this work, we computationally investigated antiviral-enzyme interactions of CYP3A4\/5 genetic variants. We also examined the deleterious impact of 751 missense single nucleotide polymorphisms (SNPs) within the CYP3A4\/5 genes. An ensemble of bioinformatics tools, [SIFT, PolyPhen-2, cadd, revel, metaLr, mutation assessor, Panther, SNP&amp;GO, PhD-SNP, SNAP, Meta-SNP, FATHMM, I-Mutant, MuPro, INPS, CONSURF, GPS 5.0, MusiteDeep and NetPhos], identified a total of 94 variants (47 SNPs in CYP3A4, 47 SNPs in CYP3A5) to potentially impact the structural integrity as well as the activity of the CYP3A4\/5 enzymes. Molecular docking was done to recognize the structural stability and binding properties of the CYP3A4\/5 protein isoforms with 3 FDA-approved antiviral drugs. Our findings indicated that the CYP3A4 gene variants; R418T, I335T and R130P and the CYP3A5 gene variants; I335T, L133P and R130Q are considered the most deleterious missense SNPs. These mutants potentially affect drug-enzyme binding and hence may alter therapeutic response. Cataloguing deleterious SNPs is essential for personalized gene-based pharmacotherapy.<\/jats:p>","DOI":"10.1038\/s41598-025-85595-x","type":"journal-article","created":{"date-parts":[[2025,1,16]],"date-time":"2025-01-16T03:44:47Z","timestamp":1736999087000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["In-silico screening and analysis of missense SNPs in human CYP3A4\/5 affecting drug-enzyme interactions of FDA-approved COVID-19 antiviral drugs"],"prefix":"10.1038","volume":"15","author":[{"given":"Amro A.","family":"Abdelazim","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamad","family":"Maged","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed I.","family":"Abdelmaksoud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sameh E.","family":"Hassanein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,1,16]]},"reference":[{"key":"85595_CR1","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1007\/s10238-020-00671-y","volume":"21","author":"M Gavriatopoulou","year":"2021","unstructured":"Gavriatopoulou, M. et al. Emerging treatment strategies for COVID-19 infection. Clin. Exp. Med. 21, 167\u2013179 (2021).","journal-title":"Clin. Exp. Med."},{"key":"85595_CR2","doi-asserted-by":"crossref","unstructured":"Biswas, M. et al. Pharmacogenetics and Precision Medicine approaches for the improvement of COVID-19 therapies. Front. Pharmacol. 13, (2022).","DOI":"10.3389\/fphar.2022.835136"},{"key":"85595_CR3","doi-asserted-by":"publisher","first-page":"102172","DOI":"10.1016\/j.pupt.2022.102172","volume":"77","author":"A AL-Taie","year":"2022","unstructured":"AL-Taie, A., B\u00fcy\u00fck, A. \u015e. & Sardas, S. Considerations into pharmacogenomics of COVID-19 pharmacotherapy: Hope, hype and reality. Pulm Pharmacol. Ther. 77, 102172 (2022).","journal-title":"Pulm Pharmacol. Ther."},{"key":"85595_CR4","doi-asserted-by":"publisher","first-page":"115","DOI":"10.37201\/req\/158.2021","volume":"35","author":"A Garc\u00eda-Lled\u00f3","year":"2022","unstructured":"Garc\u00eda-Lled\u00f3, A. et al. Pharmacological treatment of COVID-19: an opinion paper. Revista Espa\u00f1ola De Quimioterapia 35, 115\u2013130 (2022).","journal-title":"Revista Espa\u00f1ola De Quimioterapia"},{"key":"85595_CR5","doi-asserted-by":"publisher","first-page":"739","DOI":"10.3390\/ph15060739","volume":"15","author":"B Franczyk","year":"2022","unstructured":"Franczyk, B. et al. Will the Use of Pharmacogenetics Improve Treatment Efficiency in COVID-19? Pharmaceuticals 15, 739 (2022).","journal-title":"Pharmaceuticals"},{"key":"85595_CR6","doi-asserted-by":"publisher","first-page":"12808","DOI":"10.3390\/ijms222312808","volume":"22","author":"M Zhao","year":"2021","unstructured":"Zhao, M. et al. Cytochrome P450 enzymes and drug metabolism in humans. Int. J. Mol. Sci. 22, 12808 (2021).","journal-title":"Int. J. Mol. Sci."},{"key":"85595_CR7","doi-asserted-by":"publisher","first-page":"413","DOI":"10.3390\/v13030413","volume":"13","author":"I Fricke-Galindo","year":"2021","unstructured":"Fricke-Galindo, I. & Falf\u00e1n-Valencia, R. Pharmacogenetics Approach for the improvement of COVID-19 treatment. Viruses 13, 413 (2021).","journal-title":"Viruses"},{"key":"85595_CR8","doi-asserted-by":"publisher","unstructured":"Samad, L. A., Maged, M., Garo, K., Riad, B. & Elhadidi, M. The Melody of Silent Mutations: Microbiome Adaptation Across the Subduction Zone. in 5th Novel Intelligent and Leading Emerging Sciences Conference (NILES). 121\u2013125. https:\/\/doi.org\/10.1109\/NILES59815.2023.10296728 (IEEE, 2023).","DOI":"10.1109\/NILES59815.2023.10296728"},{"key":"85595_CR9","doi-asserted-by":"publisher","first-page":"e0286917","DOI":"10.1371\/journal.pone.0286917","volume":"18","author":"I Ahammad","year":"2023","unstructured":"Ahammad, I. et al. Impact of highly deleterious non-synonymous polymorphisms on GRIN2A protein\u2019s structure and function. PLoS One 18, e0286917 (2023).","journal-title":"PLoS One"},{"key":"85595_CR10","first-page":"531","volume":"13","author":"M Babayeva","year":"2020","unstructured":"Babayeva, M. & Loewy, Z. Repurposing drugs for COVID-19: Pharmacokinetics and Pharmacogenomics of Chloroquine and Hydroxychloroquine. Pharmgenomics Pers. Med. Volume 13, 531\u2013542 (2020).","journal-title":"Pharmgenomics Pers. Med. Volume"},{"key":"85595_CR11","doi-asserted-by":"publisher","first-page":"7693","DOI":"10.1080\/07391102.2021.1900918","volume":"40","author":"R Singh","year":"2022","unstructured":"Singh, R., Bhardwaj, V. K., Sharma, J., Das, P. & Purohit, R. Identification of selective cyclin-dependent kinase 2 inhibitor from the library of pyrrolone-fused benzosuberene compounds: an in silico exploration. J. Biomol. Struct. Dyn. 40, 7693\u20137701 (2022).","journal-title":"J. Biomol. Struct. Dyn."},{"key":"85595_CR12","doi-asserted-by":"publisher","first-page":"19264","DOI":"10.1038\/s41598-021-98547-y","volume":"11","author":"MN Reza","year":"2021","unstructured":"Reza, M. N. et al. Pathogenic genetic variants from highly connected cancer susceptibility genes confer the loss of structural stability. Sci. Rep. 11, 19264 (2021).","journal-title":"Sci. Rep."},{"key":"85595_CR13","doi-asserted-by":"publisher","first-page":"6774","DOI":"10.1038\/s41598-023-33764-1","volume":"13","author":"J Zhao","year":"2023","unstructured":"Zhao, J., Zhang, S., Jiang, Y., Liu, Y. & Zhu, Q. Mutation analysis of pathogenic non-synonymous single nucleotide polymorphisms (nsSNPs) in WFS1 gene through computational approaches. Sci. Rep. 13, 6774 (2023).","journal-title":"Sci. Rep."},{"key":"85595_CR14","doi-asserted-by":"publisher","first-page":"71","DOI":"10.3390\/pr9010071","volume":"9","author":"OMH Salo-Ahen","year":"2020","unstructured":"Salo-Ahen, O. M. H. et al. Molecular Dynamics simulations in Drug Discovery and Pharmaceutical Development. Processes 9, 71 (2020).","journal-title":"Processes"},{"key":"85595_CR15","doi-asserted-by":"crossref","unstructured":"Saih, A. et al. In Silico Analysis of High-Risk Missense Variants in Human ACE2 Gene and Susceptibility to SARS-CoV-2 Infection. Biomed Res Int 1\u201310 (2021). (2021).","DOI":"10.1155\/2021\/6685840"},{"key":"85595_CR16","doi-asserted-by":"crossref","unstructured":"Saih, A. et al. Computational Analysis of Missense Variants in the Human Transmembrane Protease Serine 2 (TMPRSS2) and SARS-CoV-2. Biomed Res Int 1\u201317 (2021). (2021).","DOI":"10.1155\/2021\/9982729"},{"key":"85595_CR17","doi-asserted-by":"publisher","first-page":"e1007531","DOI":"10.1371\/journal.pcbi.1007531","volume":"16","author":"J Kumuthini","year":"2020","unstructured":"Kumuthini, J. et al. Ten simple rules for providing effective bioinformatics research support. PLoS Comput. Biol. 16, e1007531 (2020).","journal-title":"PLoS Comput. Biol."},{"key":"85595_CR18","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1104\/pp.104.900153","volume":"138","author":"SY Rhee","year":"2005","unstructured":"Rhee, S. Y. & Bioinformatics Current limitations and insights for the future. Plant. Physiol. 138, 569\u2013570 (2005).","journal-title":"Plant. Physiol."},{"key":"85595_CR19","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1080\/01621459.2017.1401542","volume":"114","author":"Y A\u00eft-Sahalia","year":"2019","unstructured":"A\u00eft-Sahalia, Y. & Xiu, D. Principal component analysis of high-frequency data. J. Am. Stat. Assoc. 114, 287\u2013303 (2019).","journal-title":"J. Am. Stat. Assoc."},{"key":"85595_CR20","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1093\/cid\/ciac180","volume":"76","author":"LD Saravolatz","year":"2023","unstructured":"Saravolatz, L. D., Depcinski, S. & Sharma, M. Molnupiravir and Nirmatrelvir-Ritonavir: oral coronavirus Disease 2019 antiviral drugs. Clin. Infect. Dis. 76, 165\u2013171 (2023).","journal-title":"Clin. Infect. Dis."},{"key":"85595_CR21","doi-asserted-by":"publisher","first-page":"106708","DOI":"10.1016\/j.ijantimicag.2022.106708","volume":"61","author":"D Focosi","year":"2023","unstructured":"Focosi, D. et al. Nirmatrelvir and COVID-19: development, pharmacokinetics, clinical efficacy, resistance, relapse, and pharmacoeconomics. Int. J. Antimicrob. Agents 61, 106708 (2023).","journal-title":"Int. J. Antimicrob. Agents"},{"key":"85595_CR22","doi-asserted-by":"publisher","first-page":"D933","DOI":"10.1093\/nar\/gkac958","volume":"51","author":"FJ Martin","year":"2023","unstructured":"Martin, F. J. et al. Ensembl 2023. Nucleic Acids Res. 51, D933\u2013D941 (2023).","journal-title":"Nucleic Acids Res."},{"key":"85595_CR23","doi-asserted-by":"publisher","first-page":"D1062","DOI":"10.1093\/nar\/gkx1153","volume":"46","author":"MJ Landrum","year":"2018","unstructured":"Landrum, M. J. et al. ClinVar: improving access to variant interpretations and supporting evidence. Nucleic Acids Res. 46, D1062\u2013D1067 (2018).","journal-title":"Nucleic Acids Res."},{"key":"85595_CR24","doi-asserted-by":"publisher","first-page":"D1308","DOI":"10.1093\/nar\/gkr798","volume":"40","author":"M Cariaso","year":"2012","unstructured":"Cariaso, M. & Lennon, G. SNPedia: a wiki supporting personal genome annotation, interpretation and analysis. Nucleic Acids Res. 40, D1308\u2013D1312 (2012).","journal-title":"Nucleic Acids Res."},{"key":"85595_CR25","doi-asserted-by":"publisher","first-page":"542","DOI":"10.1002\/cpt.2321","volume":"110","author":"A Gaedigk","year":"2021","unstructured":"Gaedigk, A., Casey, S. T., Whirl-Carrillo, M., Miller, N. A. & Klein, T. E. Pharmacogene Variation Consortium: A Global Resource and Repository for Pharmacogene Variation. Clin. Pharmacol. Ther. 110, 542\u2013545 (2021).","journal-title":"Clin. Pharmacol. Ther."},{"key":"85595_CR26","doi-asserted-by":"publisher","first-page":"2729","DOI":"10.1093\/bioinformatics\/btl423","volume":"22","author":"E Capriotti","year":"2006","unstructured":"Capriotti, E., Calabrese, R. & Casadio, R. Predicting the insurgence of human genetic diseases associated to single point protein mutations with support vector machines and evolutionary information. Bioinformatics 22, 2729\u20132734 (2006).","journal-title":"Bioinformatics"},{"key":"85595_CR27","doi-asserted-by":"publisher","first-page":"675","DOI":"10.1002\/humu.21242","volume":"31","author":"S Khan","year":"2010","unstructured":"Khan, S. & Vihinen, M. Performance of protein stability predictors. Hum. Mutat. 31, 675\u2013684 (2010).","journal-title":"Hum. Mutat."},{"key":"85595_CR28","doi-asserted-by":"publisher","first-page":"2542","DOI":"10.1093\/bioinformatics\/btw192","volume":"32","author":"C Savojardo","year":"2016","unstructured":"Savojardo, C., Fariselli, P., Martelli, P. L. & Casadio, R. INPS-MD: a web server to predict stability of protein variants from sequence and structure. Bioinformatics 32, 2542\u20132544 (2016).","journal-title":"Bioinformatics"},{"key":"85595_CR29","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1007\/s12041-021-01274-6","volume":"100","author":"H Pavithran","year":"2021","unstructured":"Pavithran, H. & Kumavath, R. In silico analysis of nsSNPs in CYP19A1 gene affecting breast cancer associated aromatase enzyme. J. Genet. 100, 23 (2021).","journal-title":"J. Genet."},{"key":"85595_CR30","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1002\/pro.3779","volume":"29","author":"A Ben Chorin","year":"2020","unstructured":"Ben Chorin, A. et al. ConSurf-DB: an accessible repository for the evolutionary conservation patterns of the majority of PDB proteins. Protein Sci. 29, 258\u2013267 (2020).","journal-title":"Protein Sci."},{"key":"85595_CR31","doi-asserted-by":"publisher","first-page":"1633","DOI":"10.1002\/pmic.200300771","volume":"4","author":"N Blom","year":"2004","unstructured":"Blom, N., Sicheritz-Pont\u00e9n, T., Gupta, R., Gammeltoft, S. & Brunak, S. Prediction of post-translational glycosylation and phosphorylation of proteins from the amino acid sequence. Proteomics 4, 1633\u20131649 (2004).","journal-title":"Proteomics"},{"key":"85595_CR32","doi-asserted-by":"publisher","first-page":"2588","DOI":"10.1093\/bioinformatics\/btt447","volume":"29","author":"J Yang","year":"2013","unstructured":"Yang, J., Roy, A. & Zhang, Y. Protein\u2013ligand binding site recognition using complementary binding-specific substructure comparison and sequence profile alignment. Bioinformatics 29, 2588\u20132595 (2013).","journal-title":"Bioinformatics"},{"key":"85595_CR33","doi-asserted-by":"publisher","first-page":"W296","DOI":"10.1093\/nar\/gky427","volume":"46","author":"A Waterhouse","year":"2018","unstructured":"Waterhouse, A. et al. SWISS-MODEL: homology modelling of protein structures and complexes. Nucleic Acids Res. 46, W296\u2013W303 (2018).","journal-title":"Nucleic Acids Res."},{"key":"85595_CR34","doi-asserted-by":"publisher","first-page":"D488","DOI":"10.1093\/nar\/gkac1077","volume":"51","author":"SK Burley","year":"2023","unstructured":"Burley, S. K. et al. RCSB Protein Data Bank (RCSB.org): delivery of experimentally-determined PDB structures alongside one million computed structure models of proteins from artificial intelligence\/machine learning. Nucleic Acids Res. 51, D488\u2013D508 (2023).","journal-title":"Nucleic Acids Res."},{"key":"85595_CR35","doi-asserted-by":"crossref","unstructured":"Sevrioukova, I. F. & Poulos, T. L. Structure and mechanism of the complex between cytochrome P4503A4 and ritonavir. Proceedings of the National Academy of Sciences. 107, 18422\u201318427 (2010).","DOI":"10.1073\/pnas.1010693107"},{"key":"85595_CR36","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1124\/mol.117.109744","volume":"93","author":"MH Hsu","year":"2018","unstructured":"Hsu, M. H., Savas, U. & Johnson, E. F. The X-Ray crystal structure of the human mono-oxygenase cytochrome P450 3A5-Ritonavir Complex reveals active site differences between P450s 3A4 and 3A5. Mol. Pharmacol. 93, 14\u201324 (2018).","journal-title":"Mol. Pharmacol."},{"key":"85595_CR37","doi-asserted-by":"publisher","first-page":"e1007449","DOI":"10.1371\/journal.pcbi.1007449","volume":"16","author":"Y Haddad","year":"2020","unstructured":"Haddad, Y., Adam, V. & Heger, Z. Ten quick tips for homology modeling of high-resolution protein 3D structures. PLoS Comput. Biol. 16, e1007449 (2020).","journal-title":"PLoS Comput. Biol."},{"key":"85595_CR38","doi-asserted-by":"publisher","first-page":"2302","DOI":"10.1093\/nar\/gki524","volume":"33","author":"Y Zhang","year":"2005","unstructured":"Zhang, Y. TM-align: a protein structure alignment algorithm based on the TM-score. Nucleic Acids Res. 33, 2302\u20132309 (2005).","journal-title":"Nucleic Acids Res."},{"key":"85595_CR39","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1093\/bioinformatics\/btq662","volume":"27","author":"P Benkert","year":"2011","unstructured":"Benkert, P., Biasini, M. & Schwede, T. Toward the estimation of the absolute quality of individual protein structure models. Bioinformatics 27, 343\u2013350 (2011).","journal-title":"Bioinformatics"},{"key":"85595_CR40","doi-asserted-by":"publisher","first-page":"1765","DOI":"10.1093\/bioinformatics\/btz828","volume":"36","author":"G Studer","year":"2020","unstructured":"Studer, G. et al. QMEANDisCo\u2014distance constraints applied on model quality estimation. Bioinformatics 36, 1765\u20131771 (2020).","journal-title":"Bioinformatics"},{"key":"85595_CR41","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1107\/S0907444909042073","volume":"66","author":"VB Chen","year":"2010","unstructured":"Chen, V. B. et al. MolProbity: all-atom structure validation for macromolecular crystallography. Acta Crystallogr. D Biol. Crystallogr. 66, 12\u201321 (2010).","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"key":"85595_CR42","doi-asserted-by":"publisher","first-page":"D1373","DOI":"10.1093\/nar\/gkac956","volume":"51","author":"S Kim","year":"2023","unstructured":"Kim, S. et al. PubChem 2023 update. Nucleic Acids Res. 51, D1373\u2013D1380 (2023).","journal-title":"Nucleic Acids Res."},{"key":"85595_CR43","unstructured":"Chemical Computing Group Inc. Molecular Operating Environment (MOE). Preprint at https:\/\/www.chemcomp.com\/Products.htm (2014)."},{"key":"85595_CR44","unstructured":"Dassault Syst\u00e8mes, B. I. O. V. I. A. BIOVIA Discovery Studio. Preprint at https:\/\/www.3ds.com\/products\/biovia\/discovery-studio (2021)."},{"key":"85595_CR45","doi-asserted-by":"publisher","first-page":"548","DOI":"10.1186\/1471-2105-11-548","volume":"11","author":"H Venselaar","year":"2010","unstructured":"Venselaar, H., te Beek, T. A., Kuipers, R. K., Hekkelman, M. L. & Vriend, G. Protein structure analysis of mutations causing inheritable diseases. An e-Science approach with life scientist friendly interfaces. BMC Bioinform. 11, 548 (2010).","journal-title":"BMC Bioinform."},{"key":"85595_CR46","doi-asserted-by":"publisher","first-page":"254","DOI":"10.1007\/s00122-023-04499-4","volume":"136","author":"W Zhang","year":"2023","unstructured":"Zhang, W. et al. Mutation of a highly conserved amino acid in RPM1 causes leaf yellowing and premature senescence in wheat. Theor. Appl. Genet. 136, 254 (2023).","journal-title":"Theor. Appl. Genet."},{"key":"85595_CR47","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1016\/j.compbiolchem.2019.04.007","volume":"80","author":"M Naveed","year":"2019","unstructured":"Naveed, M., Tehreem, S. & Mehboob, M. Z. In-Silico analysis of missense SNPs in human HPPD gene associated with tyrosinemia type III and Hawkinsinuria. Comput. Biol. Chem. 80, 284\u2013291 (2019).","journal-title":"Comput. Biol. Chem."},{"key":"85595_CR48","doi-asserted-by":"publisher","first-page":"e0247249","DOI":"10.1371\/journal.pone.0247249","volume":"16","author":"MU Kakar","year":"2021","unstructured":"Kakar, M. U. et al. In silico screening and identification of deleterious missense SNPs along with their effects on CD-209 gene: an insight to CD-209 related-diseases. PLoS One 16, e0247249 (2021).","journal-title":"PLoS One"},{"key":"85595_CR49","doi-asserted-by":"publisher","first-page":"8483","DOI":"10.3390\/ijms21228483","volume":"21","author":"A Guerra-Castellano","year":"2020","unstructured":"Guerra-Castellano, A. et al. Post-translational modifications of cytochrome c in Cell Life and Disease. Int. J. Mol. Sci. 21, 8483 (2020).","journal-title":"Int. J. Mol. Sci."},{"key":"85595_CR50","doi-asserted-by":"publisher","first-page":"369","DOI":"10.2217\/pgs-2016-0179","volume":"18","author":"GX Hu","year":"2017","unstructured":"Hu, G. X. et al. Systematic screening for CYP3A4 genetic polymorphisms in a Han Chinese population. Pharmacogenomics 18, 369\u2013379 (2017).","journal-title":"Pharmacogenomics"},{"key":"85595_CR51","doi-asserted-by":"publisher","first-page":"3503","DOI":"10.2147\/DDDT.S152366","volume":"11","author":"P Fang","year":"2017","unstructured":"Fang, P. et al. Functional assessment of CYP3A4 allelic variants on lidocaine metabolism in vitro. Drug Des. Devel Ther. 11, 3503\u20133510 (2017).","journal-title":"Drug Des. Devel Ther."},{"key":"85595_CR52","doi-asserted-by":"publisher","first-page":"104755","DOI":"10.1016\/j.jbc.2023.104755","volume":"299","author":"MJ Hollander","year":"2023","unstructured":"Hollander, M. J. et al. Mutational screens highlight glycosylation as a modulator of colony-stimulating factor 3 receptor (CSF3R) activity. J. Biol. Chem. 299, 104755 (2023).","journal-title":"J. Biol. Chem."},{"key":"85595_CR53","unstructured":"CHMP. Remdesivir Gilead, INN-Remdesivir. www.ema.europa.eu\/contact (2020)."},{"key":"85595_CR54","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1007\/s12210-016-0565-z","volume":"28","author":"G Gilardi","year":"2017","unstructured":"Gilardi, G. & Di Nardo, G. Heme iron centers in cytochrome P450: structure and catalytic activity. Rend. Lincei 28, 159\u2013167 (2017).","journal-title":"Rend. Lincei"},{"key":"85595_CR55","doi-asserted-by":"publisher","first-page":"W452","DOI":"10.1093\/nar\/gks539","volume":"40","author":"NL Sim","year":"2012","unstructured":"Sim, N. L. et al. SIFT web server: predicting effects of amino acid substitutions on proteins. Nucleic Acids Res. 40, W452\u2013W457 (2012).","journal-title":"Nucleic Acids Res."},{"key":"85595_CR56","doi-asserted-by":"publisher","first-page":"2230","DOI":"10.1093\/bioinformatics\/btw222","volume":"32","author":"H Tang","year":"2016","unstructured":"Tang, H. & Thomas, P. D. PANTHER-PSEP: predicting disease-causing genetic variants using position-specific evolutionary preservation. Bioinformatics 32, 2230\u20132232 (2016).","journal-title":"Bioinformatics"},{"key":"85595_CR57","doi-asserted-by":"crossref","unstructured":"Adzhubei, I., Jordan, D. M. & Sunyaev, S. R. Predicting Functional Effect of human missense mutations using PolyPhen-2. Curr. Protoc. Hum. Genet. 76, (2013).","DOI":"10.1002\/0471142905.hg0720s76"},{"key":"85595_CR58","doi-asserted-by":"publisher","first-page":"1237","DOI":"10.1002\/humu.21047","volume":"30","author":"R Calabrese","year":"2009","unstructured":"Calabrese, R., Capriotti, E., Fariselli, P., Martelli, P. L. & Casadio, R. Functional annotations improve the predictive score of human disease-related mutations in proteins. Hum. Mutat. 30, 1237\u20131244 (2009).","journal-title":"Hum. Mutat."},{"key":"85595_CR59","doi-asserted-by":"publisher","first-page":"W247","DOI":"10.1093\/nar\/gkx369","volume":"45","author":"E Capriotti","year":"2017","unstructured":"Capriotti, E. & Fariselli, P. PhD-SNPg: a webserver and lightweight tool for scoring single nucleotide variants. Nucleic Acids Res. 45, W247\u2013W252 (2017).","journal-title":"Nucleic Acids Res."},{"key":"85595_CR60","doi-asserted-by":"publisher","first-page":"D886","DOI":"10.1093\/nar\/gky1016","volume":"47","author":"P Rentzsch","year":"2019","unstructured":"Rentzsch, P., Witten, D., Cooper, G. M., Shendure, J. & Kircher, M. CADD: predicting the deleteriousness of variants throughout the human genome. Nucleic Acids Res. 47, D886\u2013D894 (2019).","journal-title":"Nucleic Acids Res."},{"key":"85595_CR61","doi-asserted-by":"publisher","first-page":"877","DOI":"10.1016\/j.ajhg.2016.08.016","volume":"99","author":"NM Ioannidis","year":"2016","unstructured":"Ioannidis, N. M. et al. REVEL: an Ensemble Method for Predicting the pathogenicity of rare missense variants. Am. J. Hum. Genet. 99, 877\u2013885 (2016).","journal-title":"Am. J. Hum. Genet."},{"key":"85595_CR62","doi-asserted-by":"publisher","first-page":"3823","DOI":"10.1093\/nar\/gkm238","volume":"35","author":"Y Bromberg","year":"2007","unstructured":"Bromberg, Y. & Rost, B. SNAP: predict effect of non-synonymous polymorphisms on function. Nucleic Acids Res. 35, 3823\u20133835 (2007).","journal-title":"Nucleic Acids Res."},{"key":"85595_CR63","doi-asserted-by":"publisher","first-page":"2125","DOI":"10.1093\/hmg\/ddu733","volume":"24","author":"C Dong","year":"2015","unstructured":"Dong, C. et al. Comparison and integration of deleteriousness prediction methods for nonsynonymous SNVs in whole exome sequencing studies. Hum. Mol. Genet. 24, 2125\u20132137 (2015).","journal-title":"Hum. Mol. Genet."},{"key":"85595_CR64","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1016\/j.ygeno.2013.06.005","volume":"102","author":"K Frousios","year":"2013","unstructured":"Frousios, K., Iliopoulos, C. S., Schlitt, T. & Simpson, M. A. Predicting the functional consequences of non-synonymous DNA sequence variants\u2014evaluation of bioinformatics tools and development of a consensus strategy. Genomics 102, 223\u2013228 (2013).","journal-title":"Genomics"},{"key":"85595_CR65","doi-asserted-by":"publisher","first-page":"S2","DOI":"10.1186\/1471-2164-14-S3-S2","volume":"14","author":"E Capriotti","year":"2013","unstructured":"Capriotti, E., Altman, R. B. & Bromberg, Y. Collective judgment predicts disease-associated single nucleotide variants. BMC Genom. 14, S2 (2013).","journal-title":"BMC Genom."},{"key":"85595_CR66","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1002\/humu.22225","volume":"34","author":"HA Shihab","year":"2013","unstructured":"Shihab, H. A. et al. Predicting the Functional, Molecular, and phenotypic consequences of amino acid substitutions using hidden Markov models. Hum. Mutat. 34, 57\u201365 (2013).","journal-title":"Hum. Mutat."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-85595-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-85595-x","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-85595-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,16]],"date-time":"2025-01-16T04:24:36Z","timestamp":1737001476000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-85595-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,16]]},"references-count":66,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["85595"],"URL":"https:\/\/doi.org\/10.1038\/s41598-025-85595-x","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-3910067\/v1","asserted-by":"object"}]},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,16]]},"assertion":[{"value":"30 January 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 January 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 January 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"2153"}}