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Letters in Drug Design & Discovery

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ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

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Research Article

Quantum Mechanics Modeling of Oxetanes as Epoxide Hydrolase Substrates

Author(s): Meihua Tu, Jackson Ngo and Li Di*

Volume 20, Issue 9, 2023

Published on: 21 October, 2022

Page: [1372 - 1379] Pages: 8

DOI: 10.2174/1570180819666220909104037

Price: $65

Abstract

Background: Epoxide hydrolases comprise an important class of enzymes that have critical functions in the detoxification of xenobiotics and regulation of signaling molecules. In addition to epoxides, oxetanes have recently been identified as novel substrates of microsomal epoxide hydrolase (mEH). Oxetanes are common scaffolds used in medicinal chemistry design to improve potency and drug-like properties. Metabolism of oxetanes by mEH can result in high uncertainties in the prediction of human clearance due to extrahepatic contribution and large inter-individual variability. Therefore, reducing mEH-mediated oxetane metabolism is highly desirable to minimize its contribution to clearance.

Objective: The aim of the study is to evaluate whether quantum mechanical parameters are able to predict the hydrolytic rate of mEH-mediated oxetane metabolism to minimize mEH contribution to clearance.

Methods: Quantum mechanics modeling was used to evaluate the hydrolytic rate of twenty-three oxetanes by mEH. All modeling studies were performed with the Maestro software package.

Results: The results showed that LUMO energy is highly correlated with the diol formation rate of oxetane hydrolysis by mEH for structurally similar compounds, while other quantum mechanical parameters are less predictive. The data suggest that the intrinsic reactivity determines the hydrolytic rate of oxetanes. This occurs when the orientations of the molecules in the mEH active site are similar. Predictions of mEH substrate metabolic rates using LUMO are most accurate when comparing subtle structural changes without drastic changes in MW and chemotype.

Conclusion: The study suggests that LUMO energy can be used to rank-order oxetanes for their hydrolytic rate by mEH for structurally similar compounds. This finding enables the reduction of mEH-mediated oxetane metabolism based on the calculated LUMO energy.

Keywords: Microsomal epoxide hydrolase, oxetane, LUMO, quantum mechanics modeling, drug metabolism, mEH, EPHX1

« Previous Next »
[1]
Arand, M.; Cronin, A.; Adamska, M.; Oesch, F. Epoxide hydrolases: structure, function, mechanism, and assay. Methods Enzymol., 2005, 400, 569-588.
[http://dx.doi.org/10.1016/S0076-6879(05)00032-7] [PMID: 16399371]
[2]
Wang, Y.; Yang, J.; Wang, W.; Sanidad, K.Z.; Cinelli, M.A.; Wan, D.; Hwang, S.H.; Kim, D.; Lee, K.S.S.; Xiao, H.; Hammock, B.D.; Zhang, G. Soluble epoxide hydrolase is an endogenous regulator of obesity-induced intestinal barrier dysfunction and bacterial translocation. Proc. Natl. Acad. Sci. USA, 2020, 117(15), 8431-8436.
[http://dx.doi.org/10.1073/pnas.1916189117] [PMID: 32220957]
[3]
Hashimoto, K. Role of soluble epoxide hydrolase in metabolism of PUFAs in psychiatric and neurological disorders. Front. Pharmacol., 2019, 10, 36.
[http://dx.doi.org/10.3389/fphar.2019.00036] [PMID: 30761004]
[4]
Imig, J.D.; Morisseau, C. Editorial: Clinical Paths for Soluble Epoxide Hydrolase Inhibitors. Front. Pharmacol., 2020, 11, 598858.
[http://dx.doi.org/10.3389/fphar.2020.598858] [PMID: 33071800]
[5]
Chiamvimonvat, N.; Ho, C.M.; Tsai, H.J.; Hammock, B.D. The soluble epoxide hydrolase as a pharmaceutical target for hypertension. J. Cardiovasc. Pharmacol., 2007, 50(3), 225-237.
[http://dx.doi.org/10.1097/FJC.0b013e3181506445] [PMID: 17878749]
[6]
Imig, J.D.; Hammock, B.D. Soluble epoxide hydrolase as a therapeutic target for cardiovascular diseases. Nat. Rev. Drug Discov., 2009, 8(10), 794-805.
[http://dx.doi.org/10.1038/nrd2875] [PMID: 19794443]
[7]
Hammock, B.D.; McReynolds, C.B.; Wagner, K.; Buckpitt, A.; Cortes-Puch, I.; Croston, G.; Lee, K.S.S.; Yang, J.; Schmidt, W.K.; Hwang, S.H. Movement to the clinic of soluble epoxide hydrolase inhibitor EC5026 as an analgesic for neuropathic pain and for use as a nonaddictive opioid alternative. J. Med. Chem., 2021, 64(4), 1856-1872.
[http://dx.doi.org/10.1021/acs.jmedchem.0c01886] [PMID: 33550801]
[8]
Qiu, H.; Li, N.; Liu, J.Y.; Harris, T.R.; Hammock, B.D.; Chiamvimonvat, N. Soluble epoxide hydrolase inhibitors and heart failure. Cardiovasc. Ther., 2011, 29(2), 99-111.
[http://dx.doi.org/10.1111/j.1755-5922.2010.00150.x] [PMID: 20433684]
[9]
KYPROLIS (carfilzomib) for Injection. Available from: https://www. accessdata.fda.gov/drugsatfda_docs/label/2012/202714lbl.pdf
[10]
Wang, Z.; Fang, Y.; Teague, J.; Wong, H.; Morisseau, C.; Hammock, B.D.; Rock, D.A.; Wang, Z. In vitro metabolism of oprozomib, an oral proteasome inhibitor: Role of epoxide hydrolases and cytochrome P450s. Drug Metab. Dispos., 2017, 45(7), 712-720.
[http://dx.doi.org/10.1124/dmd.117.075226] [PMID: 28428366]
[11]
Fang, Y.; Johnson, H.; Anderl, J.L.; Muchamuel, T.; McMinn, D.; Morisseau, C.; Hammock, B.D.; Kirk, C.; Wang, J. Role of epoxide hydrolases and cytochrome P450s on metabolism of KZR-616, a first-in-class selective inhibitor of the immunoproteasome. Drug Metab. Dispos., 2021, 49(9), 810-821.
[http://dx.doi.org/10.1124/dmd.120.000307] [PMID: 34234005]
[12]
Rosa, M.; Bonnaillie, P.; Chanteux, H. Prediction of drug–drug interactions with carbamazepine-10,11-epoxide using a new] in vitro assay for epoxide hydrolase inhibition. Xenobiotica, 2016, 46(12), 1076-1084.
[http://dx.doi.org/10.3109/00498254.2016.1151088] [PMID: 26936324]
[13]
Lin, L.; Xie, C.; Gao, Z.; Chen, X.; Zhong, D. Metabolism and pharmacokinetics of allitinib in cancer patients: The roles of cytochrome P450s and epoxide hydrolase in its biotransformation. Drug Metab. Dispos., 2014, 42(5), 872-884.
[http://dx.doi.org/10.1124/dmd.113.056341] [PMID: 24598282]
[14]
Shah, V.; Yang, C.; Shen, Z.; Kerr, B.M.; Tieu, K.; Wilson, D.M.; Hall, J.; Gillen, M.; Lee, C.A. Metabolism and disposition of lesinurad, a uric acid reabsorption inhibitor, in humans. Xenobiotica, 2019, 49(7), 811-822.
[http://dx.doi.org/10.1080/00498254.2018.1504257] [PMID: 30117757]
[15]
Barnette, D.A.; Schleiff, M.A.; Osborn, L.R.; Flynn, N.; Matlock, M.; Swamidass, S.J.; Miller, G.P. Dual mechanisms suppress meloxicam bioactivation relative to sudoxicam. Toxicology, 2020, 440, 152478.
[http://dx.doi.org/10.1016/j.tox.2020.152478] [PMID: 32437779]
[16]
Li, X.Q.; Hayes, M.A.; Grönberg, G.; Berggren, K.; Castagnoli, N., Jr; Weidolf, L. Discovery of a novel microsomal epoxide hydrolase-catalyzed hydration of a spiro oxetane. Drug Metab. Dispos., 2016, 44(8), 1341-1348.
[http://dx.doi.org/10.1124/dmd.116.071142] [PMID: 27256986]
[17]
Toselli, F.; Fredenwall, M.; Svensson, P.; Li, X.Q.; Johansson, A.; Weidolf, L.; Hayes, M.A. Oxetane substrates of human microsomal epoxide hydrolase. Drug Metab. Dispos., 2017, 45(8), 966-973.
[http://dx.doi.org/10.1124/dmd.117.076489] [PMID: 28600384]
[18]
Toselli, F.; Fredenwall, M.; Svensson, P.; Li, X.Q.; Johansson, A.; Weidolf, L.; Hayes, M.A. Hip To Be Square: Oxetanes as design elements to alter metabolic pathways. J. Med. Chem., 2019, 62(16), 7383-7399.
[http://dx.doi.org/10.1021/acs.jmedchem.9b00030] [PMID: 31310524]
[19]
BRENDA. Available from: https://www.brenda-enzymes.org/enzyme. php? ecno=3.3.2.9
[20]
THE HUMAN PROTEIN ATLAS. Available from: https://www. proteinatlas.org/
[21]
Makmor-Bakry, M.; Sills, G.J.; Hitiris, N.; Butler, E.; Wilson, E.A.; Brodie, M.J. Genetic variants in microsomal epoxide hydrolase influence carbamazepine dosing. Clin. Neuropharmacol., 2009, 32(4), 205-212.
[http://dx.doi.org/10.1097/WNF.0b013e318187972a] [PMID: 19620853]
[22]
Daci, A.; Beretta, G.; Vllasaliu, D.; Shala, A.; Govori, V.; Norata, G.D.; Krasniqi, S. Polymorphic variants of SCN1A and EPHX1 influence plasma carbamazepine concentration, metabolism and pharmacoresistance in a population of Kosovar Albanian epileptic patients. PLoS One, 2015, 10(11), e0142408/0142401-e0142408/0142417.
[http://dx.doi.org/10.1371/journal.pone.0142408]
[23]
Zhu, X.; Yun, W.; Sun, X.; Qiu, F.; Zhao, L.; Guo, Y. Effects of major transporter and metabolizing enzyme gene polymorphisms on carbamazepine metabolism in Chinese patients with epilepsy. Pharmacogenomics, 2014, 15(15), 1867-1879.
[http://dx.doi.org/10.2217/pgs.14.142] [PMID: 25495409]
[24]
Puranik, Y.G.; Birnbaum, A.K.; Marino, S.E.; Ahmed, G.; Cloyd, J.C.; Remmel, R.P.; Leppik, I.E.; Lamba, J.K. Association of carbamazepine major metabolism and transport pathway gene polymorphisms and pharmacokinetics in patients with epilepsy. Pharmacogenomics, 2013, 14(1), 35-45.
[http://dx.doi.org/10.2217/pgs.12.180] [PMID: 23252947]
[25]
Nakajima, Y.; Saito, Y.; Shiseki, K.; Fukushima-Uesaka, H.; Hasegawa, R.; Ozawa, S.; Sugai, K.; Katoh, M.; Saitoh, O.; Ohnuma, T.; Kawai, M.; Ohtsuki, T.; Suzuki, C.; Minami, N.; Kimura, H.; Goto, Y.; Kamatani, N.; Kaniwa, N.; Sawada, J. Haplotype structures of EPHX1 and their effects on the metabolism of carbamazepine-10,11-epoxide in Japanese epileptic patients. Eur. J. Clin. Pharmacol., 2005, 61(1), 25-34.
[http://dx.doi.org/10.1007/s00228-004-0878-1] [PMID: 15692831]
[26]
Václavíková, R.; Hughes, D.J.; Souček, P. Microsomal epoxide hydrolase 1 (EPHX1): Gene, structure, function, and role in human disease. Gene, 2015, 571(1), 1-8.
[http://dx.doi.org/10.1016/j.gene.2015.07.071] [PMID: 26216302]
[27]
Dalvie, D.; Di, L. Aldehyde oxidase and its role as a drug metabolizing enzyme. Pharmacol. Ther., 2019, 201, 137-180.
[http://dx.doi.org/10.1016/j.pharmthera.2019.05.011] [PMID: 31128989]
[28]
Saenz-Méndez, P.; Katz, A.; Pérez-Kempner, M.L.; Ventura, O.N.; Vázquez, M. Structural insights into human microsomal epoxide hydrolase by combined homology modeling, molecular dynamics simulations, and molecular docking calculations. Proteins, 2017, 85(4), 720-730.
[http://dx.doi.org/10.1002/prot.25251] [PMID: 28120429]
[29]
Lewis, D.F.V.; Lake, B.G.; Bird, M.G. Molecular modelling of human microsomal epoxide hydrolase (EH) by homology with a fungal (Aspergillus niger) EH crystal structure of 1.8 Å resolution: Structure-activity relationships in epoxides inhibiting EH activity. Toxicol. In Vitro, 2005, 19(4), 517-522.
[http://dx.doi.org/10.1016/j.tiv.2004.07.001] [PMID: 15826809]
[30]
Fukui, K.; Yonezawa, T.; Shingu, H. A molecular-orbital theory of reactivity in aromatic hydrocarbons. J. Chem. Phys., 1952, 20(4), 722-725.
[http://dx.doi.org/10.1063/1.1700523]
[31]
Pearson, R.G. Absolute electronegativity and hardness correlated with molecular orbital theory. Proc. Natl. Acad. Sci. USA, 1986, 83(22), 8440-8441.
[http://dx.doi.org/10.1073/pnas.83.22.8440] [PMID: 16578791]

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