PROPOXAZEPAM INTERACTION WITH CYTOCHROMES P450 ISOFORMS BASED ON MOLECULAR DOCKING ANALYSIS
DOI:
https://doi.org/10.15407/dopovidi2023.03.096Keywords:
propoxazepam, CYP isoforms, docking, amino acid residues, interactionAbstract
Computer modeling methods allow for the optimization of the preliminary evaluation of potential drug interactions. The aim of this study was to utilize in silico modeling to predict and explain the possible interactions of propoxazepam with CYP isoenzymes at the molecular level. The iGEMDOCK v2.1 program was used to calculate the free energy of interaction and determine the amino acid residues through the molecular docking procedure. The enzymes studied were complexes of CYP isoforms with reference ligands: 1A2 (2hi4), 2B6 (5uda), 2C8 (2nnj), 2C9 (1og5), 2C19 (4gqs), 2D6 (4wnu), and 3A4 (5te8). The respective substrate molecules for each isoenzyme were phenacetin, bupropion, amodiaquine, diclofenac, S-mephenytoin, bufuralol, and midazolam with testosterone.
Propoxazepam exhibited high values of free energy of interaction with all the studied CYP isoenzymes (8.15-9.8 kcal/mole), although there were differences in the quantity of common amino acid residues participating in the interaction with individual substrates. Based on the binding energy values, it can be assumed that propoxazepam has the lowest competitive (inhibitory) effect on isoform 3A4 (with testosterone as the substrate) and on 2D6. The results of the analysis of propoxazepam interaction with different CYP isoenzymes suggest the possibility of competitive interactions with 1A2, 2C19, and 2C8, and to a lesser degree, with 2C9, 3A4, and 2B6. Additionally, propoxazepam is expected to be a substrate for these CYP isoforms.
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Reder, A., Larionov, V. & Golovenko, M. (2022). Subunit-dependent interaction of propoxazepam and its metabolite with the γ-aminobuturic acid type A receptor. EUREKA: Health Sci., 5, pp. 10-18. https://doi.org/10.21303/2504-5679.2022.002649
Golovenko, N. Ya., Larionov, V. B., Reder, A. S. & Valivodz, I. P. (2017). An еffector analysis of the interaction of propoxazepam with antagonists of GABA and glycine receptors. Neurochem. J., 11, No. 4, pp. 302-308. https://doi.org/10.1134/S1819712417040043
Voloshchuk, N. I., Reder, А. S., Golovenko, M. Y., Taran, I. V. & Pashinska, О. S. (2017). Pharmacological analysis of neurochemical antinociceptive mechanisms of propoxazepam action. Pharmacology and Drug Toxicology, No. 1, pp. 3-11 (in Ukrainian).
Pat. 119018 UA, IPC C07D 243/24, A61K 31/5513, A61P 25/04, The use of 7-brom-5-(о-chlorophenyl)-3-propoxy-1,2-dihydro-3Н-1,4-benzdiazepine-2-one for inhibition of pain syndrome on diabethicpolyneyropathy without neurotoxic action, Reder, A. S., Andronati, S. А., Golovenko, M. Ya., Larionov, V. B. & Voloshyuk, N. I., Publ. 10.04.2019 (in Ukrainian).
Pat. 11,304,956 B2 US, IPC A61K 31/5513, A61P 23/00, A61P 25/08, A61P 29/00, A61K 9/00, Use of 7-bromo-5-(o-chlorophenyl)-3-propoxy-1,2-dihydro-3H-1,4-benzodiazepin-2-one for inhibition of neuropathic pain and seizures of different etiology, Reder, A. S., Adronati, S. A., Golovenko, M. Ya., Pavlovski, V. I., Kabanova, T. A., Khalimova, O. I., Larionov, V. B. & Voloshchuk, N. I., Publ. 19.04.2022.
Wilkinson, G. R. (2005). Drug metabolism and variability among patients in drug response. N. Engl. J. Med., 352, pp.2211-2221. https://doi.org/10.1056/NEJMra032424
Sim, S. C. & Ingelman-Sundberg, M. (2010). The Human Cytochrome P450 (CYP) Allele Nomenclature website: a peer-reviewed database of CYP variants and their associated effects. Hum. Genomics, 4, No. 4, pp. 278-281. https://doi.org/10.1186/1479-7364-4-4-278
Golovenko, M. Ya. (2021). Propoxazepam is an innovative analgesic that inhibits acute and chronic pain and has polymodal mechanism of action. Visn. Nac. Acad. Nauk Ukr., No. 4, pp. 76-90 (in Ukrainian). https://doi.org/10.15407/visn2021.04.076
Yang, J.-M. & Chen, C.-C. (2004). GEMDOCK: A generic evolutionary method for molecular docking. Proteins: Structure, Function and Bioinformatics, 55, pp. 288-304. https://doi.org/10.1002/prot.20035
Yang, J.-M., Chen, Y.-F., Shen, T.-W., Kristal, B. S. & Hsu, D. F. (2005). Consensus scoring criteria for improving enrichment in virtual screening. J. Chem. Inf. Model., 45, No. 4, pp.1134-1146. https://doi.org/10.1021/ci050034w
Pelkonen, O., Turpeinen, M., Hakkola, J., Honkakoski, P., Hukkanen, J. & Raunio, H. (2008). Inhibition and induction of human cytochrome P450 enzymes: current status. Arch. Toxicol., 82, No. 10, pp. 667-715. https://doi.org/10.1007/s00204-008-0332-8
Guidance for industry: drug interaction studies — study design, data analysis, implications for dosing, and labeling. Recommendations. U.S. Department of Health and Human Services Food and Drug Administration, Center for Drug Evaluation and Research (CDER), 2012.
Stringer, R. A., Strain-Damerell, C., Nicklin, P. & Houston, J. B. (2009). Evaluation of recombinant cytochrome P450 enzymes as an in vitro system for metabolic clearance predictions. Drug Metab. Dispos., 37, No. 5, pp. 1025-1034. https://doi.org/10.1124/dmd.108.024810
Niwa, T., Narita, K., Okamoto, A., Murayama, N. & Yamazaki, H. (2019). Comparison of steroid hormone hydroxylations by and docking to human cytochromes P450 3A4 and 3A5. J. Pharm. Pharm. Sci., 22, No. 1, pp.332-339. https://doi.org/10.18433/jpps30558
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