Publication Cover
Xenobiotica
the fate of foreign compounds in biological systems
Latest Articles
149
Views
1
CrossRef citations to date
0
Altmetric
RESEARCH ARTICLE

Predicting routes of phase I and II metabolism based on quantum mechanics and machine learning

, , , &
Received 08 Aug 2023, Accepted 13 Nov 2023, Accepted author version posted online: 15 Nov 2023
Accepted author version

References

  • Bauman JN, Doran AC, King-Ahmad A, Sharma R, Walker GS, Lin J, Lin TH, Telliez JB, Tripathy S, Goosen TC, Banfield C, Malhotra BK, Dowty ME. 2022. The Pharmacokinetics, Metabolism, and Clearance Mechanisms of Abrocitinib, a Selective Janus Kinase Inhibitor, in Humans. Drug Metab. Dispos. 50(3):1106–1118.
  • Beers JL, Fu D, Jackson KD. 2021. Cytochrome P450-Catalyzed Metabolism of Cannabidiol to the Active Metabolite 7-Hydroxy-Cannabidiol Drug Metab. Dispos. 49(10):882–891.
  • Cai Y, Yang H, Li W, Liu G, Lee PW, Tang Y. 2019. Computational prediction of site of metabolism for UGT-Catalyzed reactions. J. Chem. Inf. Model. 59(3):1085–1095.
  • Choi SM, Kim Y, Lee J, Kim JH, Lee T, Min BS, Kim JA, Lee S. 2020. Characterization of hydrocoptisonine metabolites in human liver microsomes using a high-resolution quadrupole-orbitrap mass spectrometer. Xenobiotica 50(12):1423–1433.
  • Cruciani G, Carosati E, De Boeck B, Ethirajulu K, Mackie C. Howe T, Vianello R. 2005. MetaSite: understanding metabolism in human Cytochromes from the perspective of the chemist. J. Med. Chem. 48(22):6970–6979.
  • Dang NL, Hughes TB, Krishnamurthy V, Swamidass SJ. 2016. a simple model predicts UGT-mediated metabolism. Bioinformatics. 32(20):3183–3189.
  • De Gregor S, De Gregori M, Ranzani GN, Allegri M, Minella C, Regazzi M. 2012. Morphine metabolism, transport and brain disposition. Metab. Brain Dis. 27(1):1–5.
  • de Vries R, Jacobs F, Mannens G, Snoeys J, Cuyckens F, Chien C, Ward P. 2019. Apalutamide Absorption, Metabolism, and Excretion in Healthy Men, and Enzyme Reaction in Human Hepatocytes. Drug Metab. Dispos. 47(5):453–464.
  • Dixit VA, Lal LA, Agrawal SR. 2017. Recent advances in the prediction of non‐cyp450‐mediated drug metabolism. WIREs Computational Molecular Science. e1323.
  • Djoumbou-Feunang Y, Fiamoncini J, Gil-de-la-Fuente A, Greiner R, Manach C, Wishart DS. 2019. BioTransformer: a comprehensive computational tool for small molecule metabolism prediction and metabolite identification. J. Cheminf. 11(2):1–25.
  • Dowden H and Munro J. 2019. Trends in clinical success rates and therapeutic focus. Nat. Rev. Drug Discovery. 18:495–496.
  • Dumouchel JL, Argikar UA, Adams CM, Prasanna G, Ehara T, Kim S, Breen C, Mogi M. 2021. Understanding metabolism related differences in ocular efficacy of MGV354. Xenobiotica 51(1):5–14.
  • Fu CW, Lin TH. 2017. Predicting the metabolic sites by Flavin-containing Monooxygenase on drug molecules using SVM classification on computed quantum mechanics and circular fingerprints molecular descriptors. PLOS ONE. 12(1):e0169910.
  • Glaenzel U, Jin Y, Hansen R, Schroer K, Rahmanzadeh G, Pfaar U, van Lier JJ, Borell H, Meissner A, Camenisch G, Zhao S. 2020. Absorption, Distribution, Metabolism, and Excretion of Capmatinib (INC280) in Healthy Male Volunteers and In Vitro Aldehyde Oxidase Phenotyping of the Major Metabolite. Drug Metab. Dispos. 48(10):873–885.
  • Guengerich FP. 2006. Cytochrome P450s and other enzymes in drug metabolism and toxicity. An Official Journal of the American Association of Pharmaceutical Scientists. 8:E101–E111.
  • Guengerich FP. 2008. Cytochrome P450 and chemical toxicology. Chem. Res. Toxicol. 21(1):70–83.
  • Liao M, Jaw-Tsai S, Beltman J, Simmons AD, Harding TC, Xiao JJ. 2020. Evaluation of in vitro absorption, distribution, metabolism, and excretion and assessment of drug-drug interaction of rucaparib, an orally potent poly(ADP-ribose). Xenobiotica 50(9):1032–1042.
  • Hanioka N, Isobe T, Tanaka-Kagawa T, Ohkawara S. 2020. Wogonin glucuronidation in liver and intestinal microsomes of humans, monkeys, dogs, rats, and mice. Xenobiotica 50(8):906–912.
  • Hennemann M, Friedl A, Lobell M, Keldenich J, Hillisch A, Clark T, Göller AH. 2009. CypScore: quantitative prediction of reactivity toward Cytochromes P450 based on semiempirical molecular orbital theory. ChemMedChem. 4(4):657–669.
  • Hinkson IV, Madej B, Stahlberg EA. 2020. Accelerating therapeutics for opportunities in medicine: a paradigm shift in drug discovery. Front. Pharmacol. 11:1–7.
  • Hunt PA, Segall MD, Tyzack JD. 2018. WhichP450: a multi-class categorical model to predict the major metabolising CYP450 isoform for a compound. J. Comput.-Aided Mol. Des. 32:537–546.
  • Hussain Z, Zhu J, Ma X. 2021. Metabolism and hepatotoxicity of pyrazinamide, an anti-tuberculosis drug. Drug Metab. Dispos. 49(8):679–682.
  • Hutzler JM, Cerny MA, Yang YS, Asher C, Wong D, Frederick K, Gilpin K. 2014. Cynomolgus monkey as a surrogate for human aldehyde oxidase metabolism of the EGFR inhibitor BIBX1382. Drug Metab. Dispos. 42(10):1751–1760.
  • Jones S, Yarbrough AL, Shoeib A, Bush JM, Fantegrossi WE, Prather PL, Radominska-Pandya A, Fujiwara R. 2019. Enzymatic analysis of glucuronidation of synthetic cannabinoid 1-naphthyl 1-(4-fluorobenzyl)-1H-indole-3-carboxylate (FDU-PB-22). Xenobiotica 49(12):1388–1395.
  • Katyayan K, Yi P, Monk S, Cassidy K. 2020 Excretion, Mass Balance, and Metabolism of [14C]LY3202626 in Humans: An Interplay of Microbial Reduction, Reabsorption, and Aldehyde Oxidase Oxidation That Leads to an Extended Excretion Profile. Drug Metab. Dispos. 48(8):698–707.
  • Kennedy T. 1997. Managing the drug discovery/development interface. Drug Discovery Today. 2(10):436–444.
  • Kim Y, Shrestha R, Kim S, Kim JA, Lee J, Jeong TC, Kim JH, Lee S. 2020. In vitro characterization of glycyrol metabolites in human liver microsomes using HR-resolution MS spectrometer coupled with tandem mass spectrometry. Xenobiotica 50(4):380–388.
  • Lapham K, Callegari E, Cianfrogna J, Lin J, Niosi M, Orozco CC, Sharma R, Goosen TC. 2020. In Vitro Characterization of Ertugliflozin Metabolism by UDP-Glucuronosyltransferase and Cytochrome P450 Enzymes. Drug Metab. Dispos. 48(12):1350–1363.
  • van der Maaten L, Hinton G. 2008. Visualizing Data using t-SNE. J. Mach. Learn. Res. 9(86):2579 − 2605
  • Marchant CA, Briggs KA, Long A. 2008. In silico tools for sharing data and knowledge on toxicity and metabolism: Derek for Windows, Meteor, and Vitic. Toxicol. Mech. Methods. 18(2–3):177–187.
  • Matsumoto K, Hasegawa T, Ohara K, Kamei T, Koyanagi J, Akimoto M. 2021. Role of human flavin-containing monooxygenase (FMO) 5 in the metabolism of nabumetone: Baeyer–Villiger oxidation in the activation of the intermediate metabolite, 3-hydroxy nabumetone, to the active metabolite, 6-methoxy-2-naphthylacetic acid in vitro. Xenobiotica 51(2):155–166.
  • Mendez D, Gaulton A, Bento AP, Chambers J, De Veij M, Félix E, Magariños MP, Mosquera JF, Mutowo P, Nowotka M, Gordillo-Marañón M, Hunter F, Junco L, Mugumbate G, Rodriguez-Lopez M, Atkinson F, Bosc N, Radoux CJ, Segura-Cabrera A, Hersey A, Leach AR. 2019. ChEMBL: towards direct deposition of bioassay data. Nucleic Acids Res. 47(D1):D930–D940.
  • Milani N, Qiu N, Fowler S. 2022. Contribution of UGT enzymes to human drug metabolism stereoselectivity: a case study of medetomidine, RO5263397, propranolol and testosterone. Drug Metab. Dispos. 51(3):306–317.
  • Monahan BP, Ferguson CL, Killeavy ES, Lloyd BK, Troy J, Cantilena LR. 1990. Torsades de pointes occurring in association with terfenadine use. The Journal of the American Medical Association. 264(21):2788–2790.
  • Montefiori M, Jørgensen FS, Olsen L. 2017. Aldehyde Oxidase: reaction mechanism and prediction of site of metabolism. ACS Omega. 2(8):4237–4244.
  • Montefiori M, Lyngholm-Kjaerby C, Long A, Olsen L, Jørgensen FS. 2019. Fast methods for prediction of Aldehyde Oxidase-mediated site-of-metabolism. Comput. Struct. Biotechnol. J. 17:345–351.
  • Nardone-White DT, Bissada JE, Abouda AA, Jackson KD. 2021. Detoxication versus Bioactivation Pathways of Lapatinib In Vitro: UGT1A1 Catalyzes the Hepatic Glucuronidation of Debenzylated Lapatinib. Drug Metab. Dispos. 49(3):233–244.
  • Obrezanova O, Gola JMR, Champness EJ, Segall MD. 2008. Automatic QSAR modeling of ADME properties: blood–brain barrier penetration and aqueous solubility. J. Comput.-Aided Mol. Des. 22:431–440.
  • Omura K, Motoki K, Kobashi S, Miyata K, Yamano K, Iwanaga T. 2021. Identification of Human UDP-Glucuronosyltransferase and Sulfotransferase as Responsible for the Metabolism of Dotinurad, a Novel Selective Urate Reabsorption Inhibitor. Drug Metab. Dispos. 51(3):1016–1024.
  • Öeren M, Kaempf SC, Ponting DJ, Hunt PA, Segall MD. 2023. predicting regioselectivity of cytosolic Sulfotransferase metabolism for drugs. Journal of Chemical Information and Modeling. 63(11):3340–3349.
  • Öeren M, Walton PJ, Hunt PA, Ponting DJ, Segall MD. 2020. Predicting reactivity to drug metabolism: beyond P450s—modelling FMOs and UGTs. J. Comput.-Aided Mol. Des. 35:541–555.
  • Öeren M, Walton PJ, Suri J, Ponting DJ, Hunt PA, Segall MD. 2022. Predicting regioselectivity of AO, CYP, FMO, and UGT metabolism using quantum mechanical simulations and machine learning. J. Med. Chem. 65(20):14066–14081.
  • Olsen L, Montefiori M, Tran KP, Jørgensen FS. 2019. SMARTCyp 3.0: enhanced Cytochrome P450 site-of-metabolism prediction server. Bioinformatics. 35(17): 3174–3175.
  • Peng J, Lu J, Shen Q, Zheng M, Luo X, Zhu W, Jiang H, Chen K. 2013. In silico site of metabolism prediction for human UGT-catalyzed reactions. Bioinformatics 30(3): 398–405.
  • Rudik A, Dmitriev A, Lagunin A, Filimonov D, Poroikov V. 2015. SOMP: web server for in silico prediction of sites of metabolism for drug-like compounds. Bioinformatics. 31(12):2046–2048.
  • Saravanakumar A, Sadighi A, Ryu R, Akhlaghi F. 2019. Physicochemical properties, biotransformation, and transport pathways of established and newly approved medications: a systematic review of the top 200 most prescribed drugs vs. the FDA-approved drugs between 2005 and 2016. Clin. Pharmacokinet. 58:1281–1294.
  • Scheers E, Borgmans C, Keung C, Bohets H, Wynant I, Poggesi I, Cuyckens F, Leclercq L, Mamidi RNVS. 2020. Metabolism and disposition in rats, dogs, and humans of erdafitinib, an orally administered potent pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor. Xenobiotica 51(2):177–193.
  • Schlander M, Hernandez-Villafuerte K, Cheng CY, Mestre-Ferrandiz J, Baumann M. 2021. How much does it cost to research and develop a new drug? A systematic review and assessment. PharmacoEconomics. 39:1243–1269.
  • Seo KA, Bae KS, Choi YK, Choi CS, Liu KH, Shin JG. 2010. Metabolism of 1′- and 4-hydroxymidazolam by glucuronide conjugation is largely mediated by UDP-glucuronosyltransferases 1A4, 2B4, and 2B7. Drug Metab. Dispos. 38(11): 2007–2013.
  • Shih HP, Zhang X, Aronov AM. 2018. Drug discovery effectiveness from the standpoint of therapeutic mechanisms and indications. Nat. Rev. Drug Discovery. 17:19–33.
  • Šícho M, de Bruyn Kops C, Stork C, Svozil D, Kirchmair J. 2017. FAME 2: simple and effective machine learning model of Cytochrome P450 regioselectivity. The Journal of Chemical Information and Modeling. 57(8):1832–1846.
  • SMARTS - A Language for Describing Molecular Patterns. 2019. Laguna Niguel (CA): Daylight Chemical Information Systems, Inc. [accessed 2023 July 03]. https://www.daylight.com/dayhtml/doc/theory/theory.smarts.html.
  • Sorich MJ, McKinnon RA, Miners JO, Smith PA. 2006. The importance of local chemical structure for chemical metabolism by human Uridine 5'-diphosphate-glucuronosyltransferase. J. Chem. Inf. Model. 46(6):2692–2697.
  • Schuster D, Laggner C, Langer T. 2005. Why Drugs Fail - A Study on Side Effects in New Chemical Entities. Curr. Pharmaceutical Des. 11(27): 3545–3559
  • Sun D, Gao W, Hu H, Zhou S. 2022. Why 90% of clinical drug development fails and how to improve it? Acta Pharm. Sin. B. 12(7):3049–3062.
  • Surapaneni S, Yerramilli U, Bai A, Dalvie D, Brooks J, Wang X, Selkirk JV, Yan YG, Zhang P, Hargreaves R, Kumar G, Palmisano M, Tran JQ. 2021. Absorption, Metabolism, and Excretion, In Vitro Pharmacology, and Clinical Pharmacokinetics of Ozanimod, a Novel Sphingosine 1-Phosphate Receptor Modulator. Drug Metab. Dispos. 49(5):405–419.
  • Taavitsainen P, Prien O, Kähkönen M, Niehues M, Korjamo T, Denner K, Nykänen P, Vuorela A, Jungmann NA, von Bühler CJ, Koskinen M, Zurth C, Gieschen H. 2021. Metabolism and Mass Balance of the Novel Nonsteroidal Androgen Receptor Inhibitor Darolutamide in Humans. Drug Metab. Dispos. 49(6):420–433.
  • Takabe T, Imai R, Ono S. 2017. The current status of drug discovery and development as originated in united states academia: the influence of industrial and academic collaboration on drug discovery and development. Clin. Transl. Sci. 11(6):597–606.
  • Tian S, Cao X, Greiner R, Li C, Guo A, Wishart DS. 2021. CyProduct: a software tool for accurately predicting the byproducts of human Cytochrome P450 metabolism. Journal of Chemical Information and Modelling. 61(6):3128–3140.
  • Tian S, Djoumbou-Feunang Y, Greiner R, Wishart DS. 2018. CypReact: a software tool for in silico reactant prediction for human Cytochrome P450 enzymes. The Journal of Chemical Information and Modelling. 58(6):1282–1291.
  • T’jollyn H, Boussery K, Mortishire-Smith RJ, Coe K, De Boeck B, Van Bocxlaer JF, Mannens G. 2011. Evaluation of three state-of-the-art metabolite prediction software packages (Meteor, MetaSite, and Stardrop) through independent and synergistic use. Drug Metab. Dispos. 39(11):2066–2075.
  • Tyzack JD, Hunt PA, Segall MD. 2016. Predicting regioselectivity and lability of cytochrome P450 metabolism using quantum mechanical simulations. J. Chem. Inf. Model. 56(11):2180–2193.
  • Vaillancourt J, Turcotte V, Caron P, Villeneuve L, Lacombe L, Pouliot F, Lévesque É, Guillemette C. 2020. Glucuronidation of Abiraterone and its Pharmacologically Active Metabolites by UGT1A4, Influence of Polymorphic Variants and their Potential as Inhibitors of Steroid Glucuronidation. Drug Metab. Dispos. 48(2):75–84.
  • Veeravalli S, Phillips IR, Freire RT, Varshavi D, Everett JR, Shephard EA. 2020. Flavin-Containing Monooxygenase 1 (FMO1) Catalyzes the Production of Taurine from Hypotaurine. Drug Metab. Dispos. 48(5):378–385.
  • Weiss HM, Langenickel T, Cain M, Kulkarni S, Shah B, Vemula J, Rahmanzadeh G, Poller B. 2021. Clinical Investigation of Metabolic and Renal Clearance Pathways Contributing to the Elimination of Fevipiprant Using Probenecid as Perpetrator. Drug Metab. Dispos. 49(5):389–394.
  • Williams JA, Hyland R, Jones BC, Smith DA, Hurst S, Goosen TC, Peterkin V, Koup JR, Ball SE. 2004. Drug-drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCI/AUC) ratios. Drug Metab. Dispos. 32(11):1201–1208.
  • Wouters OJ, McKee M, Luyten J. 2020. Estimated research and development investment needed to bring a new medicine to market, 2009-2018. Journal of the American Medical Association. 323(9): 844–853.
  • Yamane M, Igarashi F, Yamauchi T, Nakagawa T. 2021. Main contribution of UGT1A1 and CYP2C9 in the metabolism of UR-1102, a novel agent for the treatment of gout. Xenobiotica 51(1):61–71.
  • Yu C. 2020. Metabolism and in vitro drug–drug interaction assessment of viloxazine. Xenobiotica 50(11):1285–1300.
  • Zanger UM and Schwab M. 2013. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol. Ther. 138(1):103–141.
  • Zaretzki J, Matlock M, Swamidass SJ. 2013. XenoSite: Accurately Predicting CYP-Mediated Sites of Metabolism with Neural Networks XenoSite: accurately predicting CYP-mediated sites of metabolism with neural networks. The Journal of Chemical Information and Modelling. 53(12):3373–3383.
  • Zhang L, Poland B, Green M, Wong S, Slatter JG. 2022. A population pharmacokinetic-pharmacodynamic model of navtemadlin, its glucuronide metabolite (M1) and serum macrophage inhibitory cykokine-1 (MIC-1). Xenobiotica 52(6):555–566.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.