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Cytochrome P450 3A4, a key isoform of the cytochrome P450 superfamily, is involved in the metabolism of over 50% of xenobiotics. Flavonoids, present in various foods and supplements, exhibit diverse biological activities influenced by the structural modifications in their scaffold. Methods: Fifteen polyhydroxy-flavonoid compounds were firstly tested by a high-throughput fluorimetric method for their ability to inhibit CYP3A4, where scutellarein and gossypetin were assessed for the first time. A molecular docking analysis was performed for the most active inhibitors to gain insight on their interaction with the active site of the enzyme. Results: Baicalein, luteolin, and scutellarein were the most potent flavones, presenting an IC50 of 15 \u00b1 5, 31 \u00b1 10, and 19 \u00b1 7 \u03bcmol\/L, respectively. Gossypetin, herbacetin, and quercetin were the most potent flavonols with IC50 of 40 \u00b1 8, 32 \u00b1 8, and 23 \u00b1 5 \u03bcmol\/L, respectively. The molecular docking analysis showed that hydroxyl groups at C6, C7, C8 (ring A), and C3\u2019 (ring B) on the flavone structure affect CYP3A4 enzyme catalysis by binding to its substrate-binding site as strong as known antiviral and antifungal drugs. Conclusions: Binding to the enzyme\u2019s active site with a strength comparable to known antifungal and antiviral drugs, baicalein and scutellarein were identified as the most active flavonoids. The vicinal hydroxyls in those molecules were pivotal to positioning and stabilization in the catalytic site pocket.<\/jats:p>","DOI":"10.3390\/biomedicines13030655","type":"journal-article","created":{"date-parts":[[2025,3,7]],"date-time":"2025-03-07T07:05:46Z","timestamp":1741331146000},"page":"655","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["How Plant Polyhydroxy Flavonoids Can Hinder the Metabolism of Cytochrome 3A4"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2024-4021","authenticated-orcid":false,"given":"Carina S. P.","family":"Vieira","sequence":"first","affiliation":[{"name":"Associated Laboratory for Green Chemistry (LAQV), Network of Chemistry and Technology (REQUIMTE), Laboratory of Applied Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9114-9967","authenticated-orcid":false,"given":"Marisa","family":"Freitas","sequence":"additional","affiliation":[{"name":"Associated Laboratory for Green Chemistry (LAQV), Network of Chemistry and Technology (REQUIMTE), Laboratory of Applied Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1391-2143","authenticated-orcid":false,"given":"Andreia","family":"Palmeira","sequence":"additional","affiliation":[{"name":"Laboratory of Organic and Pharmaceutical Chemistry (LQOF), Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal"},{"name":"Interdisciplinary Centre of Marine and Environmental Research (CIIMAR), 4450-208 Matosinhos, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6424-0976","authenticated-orcid":false,"given":"Eduarda","family":"Fernandes","sequence":"additional","affiliation":[{"name":"Associated Laboratory for Green Chemistry (LAQV), Network of Chemistry and Technology (REQUIMTE), Laboratory of Applied Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5348-4924","authenticated-orcid":false,"given":"Alberto N.","family":"Ara\u00fajo","sequence":"additional","affiliation":[{"name":"Associated Laboratory for Green Chemistry (LAQV), Network of Chemistry and Technology (REQUIMTE), Laboratory of Applied Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"854015","DOI":"10.1155\/2015\/854015","article-title":"Interactions between CYP3A4 and Dietary Polyphenols","volume":"2015","author":"Basheer","year":"2015","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Kondza, M., Bojic, M., Tomic, I., Males, Z., Rezic, V., and Cavar, I. (2021). Characterization of the CYP3A4 Enzyme Inhibition Potential of Selected Flavonoids. Molecules, 26.","DOI":"10.3390\/molecules26103018"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Ung, Y.T., Ong, C.E., and Pan, Y. (2018). Current High-Throughput Approaches of Screening Modulatory Effects of Xenobiotics on Cytochrome P450 (CYP) Enzymes. High-Throughput, 7.","DOI":"10.3390\/ht7040029"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1016\/j.fct.2009.10.041","article-title":"Inhibitory effects of polyphenols on human cytochrome P450 3A4 and 2C9 activity","volume":"48","author":"Kimura","year":"2010","journal-title":"Food Chem. Toxicol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.toxlet.2018.05.008","article-title":"Drug interaction study of flavonoids toward CYP3A4 and their quantitative structure activity relationship (QSAR) analysis for predicting potential effects","volume":"294","author":"Li","year":"2018","journal-title":"Toxicol. Lett."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"9713","DOI":"10.1080\/07391102.2021.1932603","article-title":"On the inhibition of cytochrome P450 3A4 by structurally diversified flavonoids","volume":"40","author":"Mitrasinovic","year":"2022","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"33","DOI":"10.5562\/cca3652","article-title":"Inhibitory Effect of Acacetin, Apigenin, Chrysin and Pinocembrin on Human Cytochrome P450 3A4","volume":"93","author":"Kondza","year":"2020","journal-title":"Croat. Chem. Acta"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3671","DOI":"10.1007\/s00204-020-02936-7","article-title":"Inhibition and induction of CYP enzymes in humans: An update","volume":"94","author":"Hakkola","year":"2020","journal-title":"Arch. Toxicol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Iacopetta, D., Ceramella, J., Catalano, A., Scali, E., Scumaci, D., Pellegrino, M., Aquaro, S., Saturnino, C., and Sinicropi, M.S. (2023). Impact of Cytochrome P450 Enzymes on the Phase I Metabolism of Drugs. Appl. Sci., 13.","DOI":"10.3390\/app13106045"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Carrascal-Laso, L., Franco-Mart\u00edn, M.A., Garc\u00eda-Berrocal, M.B., Marcos-Vadillo, E., Sanchez-Iglesias, S., Lorenzo, C., Sanchez-Mart\u00edn, A., Ramos-Gallego, I., Garc\u00eda-Salgado, M.J., and Isidoro-Garc\u00eda, M. (2020). Application of a Pharmacogenetics-Based Precision Medicine Model (5SPM) to Psychotic Patients That Presented Poor Response to Neuroleptic Therapy. J. Pers. Med., 10.","DOI":"10.3390\/jpm10040289"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1002\/jps.23382","article-title":"Flavonoids and polymer derivatives as CYP3A4 inhibitors for improved oral drug bioavailability","volume":"102","author":"Fasinu","year":"2013","journal-title":"J. Pharm. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"162750","DOI":"10.1155\/2013\/162750","article-title":"Chemistry and Biological Activities of Flavonoids: An Overview","volume":"2013","author":"Kumar","year":"2013","journal-title":"Sci. World J."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"111442","DOI":"10.1016\/j.foodres.2022.111442","article-title":"Flavonoids: Food associations, therapeutic mechanisms, metabolism and nanoformulations","volume":"157","author":"Kaushal","year":"2022","journal-title":"Food Res. Int."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1016\/j.foodchem.2005.10.028","article-title":"Quercetin content in some food and herbal samples","volume":"100","author":"Wach","year":"2007","journal-title":"Food Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"109623","DOI":"10.1016\/j.foodres.2020.109623","article-title":"Effect of polyphenols on HER2-positive breast cancer and related miRNAs: Epigenomic regulation","volume":"137","author":"Zabaleta","year":"2020","journal-title":"Food Res. Int."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.1080\/10408347.2022.2105641","article-title":"Bioactive Flavonoids: A Comprehensive Review on Pharmacokinetics and Analytical Aspects","volume":"54","author":"Billowria","year":"2024","journal-title":"Crit. Rev. Anal. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"137115","DOI":"10.1016\/j.foodchem.2023.137115","article-title":"Opportunities and challenges in enhancing the bioavailability and bioactivity of dietary flavonoids: A novel delivery system perspective","volume":"430","author":"Yuan","year":"2024","journal-title":"Food Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"423","DOI":"10.3945\/an.116.012948","article-title":"Flavones: Food Sources, Bioavailability, Metabolism, and Bioactivity","volume":"8","author":"Hostetler","year":"2017","journal-title":"Adv. Nutr."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1426","DOI":"10.1016\/j.bcp.2007.11.012","article-title":"Flavonoids diosmetin and luteolin inhibit midazolam metabolism by human liver microsomes and recombinant CYP 3A4 and CYP3A5 enzymes","volume":"75","author":"Quintieri","year":"2008","journal-title":"Biochem. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1002\/chir.21005","article-title":"Enantiomers of Naringenin as Pleiotropic, Stereoselective Inhibitors of Cytochrome P450 Isoforms","volume":"23","author":"Lu","year":"2011","journal-title":"Chirality"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/s43094-023-00477-1","article-title":"Naringenin alters the pharmacokinetics of ranolazine in part through the inhibition of cytochrome P450 (3A4) and P-glycoprotein","volume":"9","author":"Alotaibi","year":"2023","journal-title":"Future J. Pharm. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"541","DOI":"10.2478\/acph-2019-0039","article-title":"Screening of flavonoid aglycons\u2019 metabolism mediated by the human liver cytochromes P450","volume":"69","author":"Benkovic","year":"2019","journal-title":"Acta Pharm."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"13682","DOI":"10.1073\/pnas.0603236103","article-title":"Structural basis for ligand promiscuity in cytochrome P450 3A4","volume":"103","author":"Ekroos","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1093\/imanum\/drl016","article-title":"A descent modified Polak-Ribiere-Polyak conjugate gradient method and its global convergence","volume":"26","author":"Zhang","year":"2006","journal-title":"IMA J. Numer. Anal."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1007\/s10822-010-9352-6","article-title":"Ligand docking and binding site analysis with PyMOL and Autodock\/Vina","volume":"24","author":"Seeliger","year":"2010","journal-title":"J. Comput.-Aided Mol. Des."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading","volume":"31","author":"Trott","year":"2010","journal-title":"J. Comput. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1055\/a-1502-7131","article-title":"Herbacetin Broadly Blocks the Activities of CYP450s by Different Inhibitory Mechanisms","volume":"88","author":"Qian","year":"2022","journal-title":"Planta Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1080\/13880209.2021.1942927","article-title":"Baicalein inhibits the pharmacokinetics of simvastatin in rats via regulating the activity of CYP3A4","volume":"59","author":"Meng","year":"2021","journal-title":"Pharm. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1016\/S1734-1140(11)70624-7","article-title":"Effects of the antioxidant baicalein on the pharmacokinetics of nimodipine in rats: A possible role of P-glycoprotein and CYP3A4 inhibition by baicalein","volume":"63","author":"Cho","year":"2011","journal-title":"Pharmacol. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1248\/bpb.32.671","article-title":"The Structure-Activity Correlation on the Inhibitory Effects of Flavonoids on Cytochrome P450 3A Activity","volume":"32","author":"Tsujimoto","year":"2009","journal-title":"Biol. Pharm. Bull."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2237","DOI":"10.1271\/bbb.110328","article-title":"Effective Cytochrome P450 (CYP) Inhibitor Isolated from Thyme (Thymus saturoides) Purchased from a Japanese Market","volume":"75","author":"Brahmi","year":"2011","journal-title":"Biosci. Biotechnol. Biochem."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Kim, J.M., Seo, S.W., Han, D.G., Yun, H., and Yoon, I.S. (2021). Assessment of Metabolic Interaction between Repaglinide and Quercetin via Mixed Inhibition in the Liver: In Vitro and In Vivo. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13060782"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1873","DOI":"10.1002\/ptr.5220","article-title":"Evaluation of Inhibitory Effects of Caffeic acid and Quercetin on Human Liver Cytochrome P450 Activities","volume":"28","author":"Rastogi","year":"2014","journal-title":"Phytother. Res."},{"key":"ref_34","first-page":"217","article-title":"Inhibition of human CYP3A4 activity by grapefruit flavonoids, furanocoumarins and related compounds","volume":"4","author":"Ho","year":"2001","journal-title":"J. Pharm. Pharm. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1211\/0022357044021","article-title":"Inhibition of human cytochromes P450 by components of Ginkgo biloba","volume":"56","author":"Weemhoff","year":"2004","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1016\/j.bbrc.2004.04.139","article-title":"Inhibition of human P450 enzymes by multiple constituents of the Ginkgo biloba extract","volume":"318","author":"Gaudineau","year":"2004","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Lee, J., Beers, J.L., Geffert, R.M., and Jackson, K.D. (2024). A Review of CYP-Mediated Drug Interactions: Mechanisms and In Vitro Drug-Drug Interaction Assessment. Biomolecules, 14.","DOI":"10.3390\/biom14010099"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1573","DOI":"10.1021\/ci300118x","article-title":"Cytochrome P450 3A4 Inhibition by Ketoconazole: Tackling the Problem of Ligand Cooperativity Using Molecular Dynamics Simulations and Free-Energy Calculations","volume":"52","author":"Bren","year":"2012","journal-title":"J. Chem. Inf. Model."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Basheer, L., Schultz, K., and Kerem, Z. (2016). Inhibition of cytochrome P450 3A by acetoxylated analogues of resveratrol in in vitro and in silico models. Sci. Rep., 6.","DOI":"10.1038\/srep31557"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.biopha.2015.05.018","article-title":"Molecular docking of chemotherapeutic agents to CYP3A4 in non-small cell lung cancer","volume":"73","author":"Subhani","year":"2015","journal-title":"Biomed. Pharmacother."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Kiani, Y.S., Ranaghan, K.E., Jabeen, I., and Mulholland, A.J. (2019). Molecular Dynamics Simulation Framework to Probe the Binding Hypothesis of CYP3A4 Inhibitors. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20184468"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1124\/dmd.105.007625","article-title":"In silico and in vitro screening for inhibition of cytochrome P450CYP3A4 by comedications commonly used by patients with cancer","volume":"34","author":"Yu","year":"2006","journal-title":"Drug Metab. Dispos."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1021\/acs.molpharmaceut.7b00957","article-title":"Inhibition of Human CYP3A4 by Rationally Designed Ritonavir-Like Compounds: Impact and Interplay of the Side Group Functionalities","volume":"15","author":"Samuels","year":"2018","journal-title":"Mol. Pharm."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Samuels, E.R., and Sevrioukova, I.F. (2022). Interaction of CYP3A4 with Rationally Designed Ritonavir Analogues: Impact of Steric Constraints Imposed on the Heme-Ligating Group and the End-Pyridine Attachment. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23137291"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Patel, V., Ananthula, S., Shah, P., Lavin, E.S., and Sikora, A. (2024). Identification of the binding residues on CYP3A4 to Naringin using Protein Modelling and Docking. J. Biol. Chem., 300.","DOI":"10.1016\/j.jbc.2024.105918"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"345","DOI":"10.2133\/dmpk.DMPK-12-RG-133","article-title":"Three-dimensional Quantitative Structure-Activity Relationship Analysis of Inhibitors of Human and Rat Cytochrome P4503A Enzymes","volume":"28","author":"Handa","year":"2013","journal-title":"Drug Metab. Pharmacokinet."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1111\/bcpt.13552","article-title":"Effects of saikosaponin-d on CYP3A4 in HepaRG cell and protein-ligand docking study","volume":"128","author":"Li","year":"2021","journal-title":"Basic Clin. Pharmacol. Toxicol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.3897\/pharmacia.69.e96626","article-title":"In vitro effects and in silico analysis of newly synthetized pyrrole derivatives on the activity of different isoforms of Cytochrome P450 CYP1A2, CYP2D6 and CYP3A4","volume":"69","author":"Angelov","year":"2022","journal-title":"Pharmacia"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1016\/0076-6879(90)86128-I","article-title":"Flavonoids as antioxidants-Determination of radical-scavenging efficiences","volume":"186","author":"Bors","year":"1990","journal-title":"Methods Enzymol."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Mustapic, D.S., Debeljak, Z., Males, Z., and Bojic, M. (2018). The Inhibitory Effect of Flavonoid Aglycones on the Metabolic Activity of CYP3A4 Enzyme. Molecules, 23.","DOI":"10.3390\/molecules23102553"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1186","DOI":"10.1039\/C4FO00007B","article-title":"Reactivity of food phenols with iron and copper ions: Binding, dioxygen activation and oxidation mechanisms","volume":"5","author":"Nkhili","year":"2014","journal-title":"Food Funct."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"9982","DOI":"10.1039\/c0dt00752h","article-title":"Kinetics of iron oxidation upon polyphenol binding","volume":"39","author":"Perron","year":"2010","journal-title":"Dalton Trans."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/j.toxlet.2019.11.016","article-title":"Heterotropic activation of flavonoids on cytochrome P450 3A4: A case example of alleviating dronedarone-induced cytotoxicity","volume":"319","author":"Bai","year":"2020","journal-title":"Toxicol. Lett."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Kej\u00edk, Z., Kapl\u00e1nek, R., Masar\u00edk, M., Babula, P., Matkowski, A., Filipensky, P., Vesel\u00e1, K., Gburek, J., Sykora, D., and Mart\u00e1sek, P. (2021). Iron Complexes of Flavonoids-Antioxidant Capacity and Beyond. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22020646"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"131292","DOI":"10.1016\/j.foodchem.2021.131292","article-title":"Unravelling discolouration caused by iron-flavonoid interactions: Complexation, oxidation, and formation of networks","volume":"370","author":"Bijlsma","year":"2022","journal-title":"Food Chem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"7730","DOI":"10.1080\/10408398.2021.1917508","article-title":"Absorption, metabolism and bioavailability of flavonoids: A review","volume":"62","author":"Chen","year":"2022","journal-title":"Crit. Rev. Food Sci. Nutr."},{"key":"ref_57","first-page":"151","article-title":"Bioavailability and metabolism of flavonoids","volume":"47","author":"Ondrejovic","year":"2008","journal-title":"J. Food Nutr. Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1006\/abbi.2001.2401","article-title":"Covalent alteration of the CYP3A4 active site: Evidence for multiple substrate binding domains","volume":"391","author":"Schrag","year":"2001","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Yim, S.K., Kim, K., Chun, S., Oh, T., Jung, W., Jung, K., and Yun, C.H. (2020). Screening of Human CYP1A2 and CYP3A4 Inhibitors from Seaweed In Silico and In Vitro. Mar. Drugs, 18.","DOI":"10.3390\/md18120603"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"38091","DOI":"10.1074\/jbc.C400293200","article-title":"The structure of human microsomal cytochrome P450 3A4 determined by X-ray crystallography to 2.05-\u00c5 resolution","volume":"279","author":"Yano","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2036","DOI":"10.1016\/j.bbapap.2010.06.008","article-title":"Analysis of binding modes of ligands to multiple conformations of CYP3A4","volume":"1804","author":"Teixeira","year":"2010","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"3116","DOI":"10.1039\/C2DT31833D","article-title":"Understanding the mechanism of cytochrome P450 3A4: Recent advances and remaining problems","volume":"42","author":"Sevrioukova","year":"2013","journal-title":"Dalton Trans."},{"key":"ref_63","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_64","doi-asserted-by":"crossref","unstructured":"Beck, T.C., Beck, K.R., Morningstar, J., Benjamin, M.M., and Norris, R.A. (2021). Descriptors of Cytochrome Inhibitors and Useful Machine Learning Based Methods for the Design of Safer Drugs. Pharmaceuticals, 14.","DOI":"10.3390\/ph14050472"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Xu, X.-y., Chen, J., Chen, Z.-x., Zhang, Z.-y., Jin, L.-h., Luo, J.-c., Zhong, Y.-s., Zhou, Q., and Qian, J.-c. (2025). CYP3A4 activity variations can lead to stratified metabolism of abemaciclib. Int. J. Biol. Macromol., 304.","DOI":"10.1016\/j.ijbiomac.2025.140836"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Samuels, E.R., and Sevrioukova, I.F. (2025). Evaluation of Larger Side-Group Functionalities and the Side\/End-Group Interplay in Ritonavir-Like Inhibitors of CYP3A4. Chem. Biol. Drug Des., 105.","DOI":"10.1111\/cbdd.70043"},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Alsfouk, A.A., Faris, A., Cacciatore, I., and Alnajjar, R. (2024). Development of novel CDK9 and CYP3A4 inhibitors for cancer therapy through field and computational approaches. Front. Chem., 12.","DOI":"10.3389\/fchem.2024.1473398"},{"key":"ref_68","first-page":"858","article-title":"Molecular Docking Studies on Binding Sites, Interactions and Stability of Globular Protein, Ovalbumin (OVA) with 4-Dicyanomethylene-2-methyl-6-(4-dimethylaminostyryl)-4H-pyran (DCDAP) Dye in presence of various Flavonoids of Psidium guajava","volume":"14","author":"Haridas","year":"2024","journal-title":"J. Chem. Health Risks"},{"key":"ref_69","first-page":"292","article-title":"Molecular Docking Studies on the Binding Interaction and Stability of Ovalbumin with 4-Dicyanomethylene-2,6-Dimethyl-4H-Pyran (DDPYRA) Dye in the Presence of Flavonoids","volume":"14","author":"Yogalaxshmi","year":"2024","journal-title":"J. Chem. Health Risks"},{"key":"ref_70","first-page":"505","article-title":"Exploring the Binding Stability and Sub Domains of Bovine Serum Albumin (BSA) In the Presence of Phenolic Derivatives of Benzoic Acids and Cinnamic Acids Through Molecular Docking Approach","volume":"14","author":"Rajagopalan","year":"2024","journal-title":"J. Chem. Health Risks"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"141297","DOI":"10.1016\/j.molstruc.2024.141297","article-title":"Structural interaction relationship of six edible flavonoids with CYP3A4 based on spectroscopic and computer simulation","volume":"1328","author":"Du","year":"2025","journal-title":"J. Mol. Struct."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1654","DOI":"10.1002\/bio.4553","article-title":"Comparative study of the interaction mechanism of astilbin, isoastilbin, and neoastilbin with CYP3A4","volume":"38","author":"Tao","year":"2023","journal-title":"Luminescence"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"3988","DOI":"10.1002\/ptr.7547","article-title":"Molecular dynamics simulation and in vitro evaluation of herb-drug interactions involving dietary polyphenols and CDK inhibitors in breast cancer chemotherapy","volume":"36","author":"Patil","year":"2022","journal-title":"Phytother. Res."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1007\/s10895-023-03258-4","article-title":"Inhibition Effect of Okanin Toward Human Cytochrome P450 3A4 and 2D6 with Multi-spectroscopic Studies and Molecular Docking","volume":"34","author":"Wang","year":"2024","journal-title":"J. Fluoresc."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/j.molimm.2013.05.183","article-title":"Three-dimensional quantitative structure-activity relationship and docking studies on a series of anthocyanin derivatives as cytochrome P450 3A4 inhibitors","volume":"56","author":"Shityakov","year":"2013","journal-title":"Mol. Immunol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"2125","DOI":"10.1021\/acs.chemrestox.9b00307","article-title":"In Vitro Metabolism of Auriculasin and Its Inhibitory Effects on Human Cytochrome P450 and UDP-Glucuronosyltransferase Enzymes","volume":"32","author":"Shi","year":"2019","journal-title":"Chem. Res. Toxicol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1921","DOI":"10.1021\/tx100286d","article-title":"Structure-Function Relationships of Inhibition of Human Cytochromes P450 1A1, 1A2, 1B1, 2C9, and 3A4 by 33 Flavonoid Derivatives","volume":"23","author":"Shimada","year":"2010","journal-title":"Chem. Res. Toxicol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"2555","DOI":"10.1021\/ci500319f","article-title":"Structural Protein-Ligand Interaction Fingerprints (SPLIF) for Structure-Based Virtual Screening: Method and Benchmark Study","volume":"54","author":"Da","year":"2014","journal-title":"J. Chem Inf. Model."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1329","DOI":"10.1124\/dmd.118.082032","article-title":"Comparison of Antifungal Azole Interactions with Adult Cytochrome P450 3A4 versus Neonatal Cytochrome P450 3A7","volume":"46","author":"Godamudunage","year":"2018","journal-title":"Drug Metab. 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