Theoretical study of chlorpromazine Drug and its metabolites: DFT calculation and QSAR toolbox investigation
Keywords:
chlorpromazine, metabolites, DFT, QSAR ModelAbstract
Introduction: Pharmaceutical compounds are among the most important products for the treatment and prevention of various problems. However, their excess or incompatibility with other compounds can harm human health. These compounds include, in particular, psychological and neurological effects, which have recently become widely used to treat schizophrenia and behavioraldisorders.
Methods: This work aims to study chlorpromazine, a pharmaceutical compound used as an antipsychotic in psychological and neurological conditions, as well as its characteristics, chemical and biological properties, and interactions with other compounds. The drug and its metabolites induce the human body to avoid them, as well as the resulting hot flashes. This theoretical study was carried out using molecular modelling with Gaussian program. Density functional theory (DFT) was used to identify the geometric, energetic, and reactivity properties of the systems studied. To study the biological activity and toxicity of our compounds, we used the QSAR-Toxtree program.
Results: Our results allowed us to determine the most biologically active compound and conclude that the resulting compounds are likely to produce more or less toxic compounds. In light of these results, it can be stated that: the compound chlorpromazine is more biologically stable compared to its metabolites, which confirms that it is an active substance in medical applications. In general, we found that all the compounds studied have chemical and biological activity and are combined with each other in the resulting potential toxicity.
References
− Abernathy, C. O., Lukacs, L., & Zimmerman, H. J. (1977). Adverse effects of chlorpromazine metabolites on isolated hepatocytes. Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N.Y.), 155(4), 474–478. https://doi.org/10.3181/00379727-155-39833
− Adnanhatem, O., Suhail, F., & Juda, A. (2016). Computational and polarographic study on drug-receptor interaction for carvedilol. International Journal of Pharmacy and Pharmaceutical Sciences. https://www.semanticscholar.org/paper/computational-and-polarographic-study-on-for-adnanhatem-suhail
− Amaral, L., Kristiansen, J. E., Viveiros, M., & Atouguia, J. (2001). Activity of phenothiazines against antibiotic-resistant Mycobacterium tuberculosis: A review supporting further studies that may elucidate the potential use of thioridazine as anti-tuberculosis therapy. Journal of Antimicrobial Chemotherapy, 47(5), 505–511. https://doi.org/10.1093/jac/47.5.505
− Antipsychotic agents in the treatment of bipolar mania—Tohen—2009—bipolar disorders—Wiley Online Library. (n.d.). Retrieved March 29, 2025, from https://onlinelibrary.wiley.com/doi/full/10.1111/j.1399-5618.2009.00710.x
− Becke, A. D. (1993). Density‐functional thermochemistry. III. The role of exact exchange. The Journal of Chemical Physics, 98(7), 5648–5652. https://doi.org/10.1063/1.464913
− Ben-Yoav, H., Winkler, T. E., Kim, E., Chocron, S. E., Kelly, D. L., Payne, G. F., & Ghodssi, R. (2014). Redox cycling-based amplifying electrochemical sensor for in situ clozapine antipsychotic treatment monitoring. Electrochimica Acta, 130, 497–503. https://doi.org/10.1016/j.electacta.2014.03.045
− Bussy, U., Boisseau, R., Thobie-Gautier, C., & Boujtita, M. (2015). Electrochemistry-mass spectrometry to study reactive drug metabolites and CYP450 simulations. TrAC Trends in Analytical Chemistry, 70, 67–73. https://doi.org/10.1016/j.trac.2015.02.017
− Capuano, B., Crosby, I. T., Lloyd, E. J., Podloucka, A., & Taylor, D. A. (2008). Synthesis and Preliminary Pharmacological Evaluation of 4′-Arylalkyl Analogues of Clozapine. IV.* The Effects of Aromaticity and Isosteric Replacement. Australian Journal of Chemistry, 61(12), 930–940. https://doi.org/10.1071/CH08307
− Capuano, B., Crosby, I. T., McRobb, F. M., Podloucka, A., Taylor, D. A., Vom, A., & Yuriev, E. (2010). The Synthesis and Preliminary Pharmacological Evaluation of a Series of Substituted 4′-Phenoxypropyl Analogues of the Atypical Antipsychotic Clozapine. Australian Journal of Chemistry, 63(1), 116–124. https://doi.org/10.1071/CH09345
− Chlorpromazine-induced increase in dipalmitoylphosphatidylserine surface area in monolayers at room temperature—PubMed. (n.d.). Retrieved March 29, 2025, from https://pubmed.ncbi.nlm.nih.gov/11274967/
− Committee, E. S., More, S. J., Bampidis, V., Benford, D., Bragard, C., Halldorsson, T. I., Hernández-Jerez, A. F., Hougaard Bennekou, S., Koutsoumanis, K. P., Machera, K., Naegeli, H., Nielsen, S. S., Schlatter, J. R., Schrenk, D., Silano, V., Turck, D., Younes, M., Gundert-Remy, U., Kass, G. E. N., … Wallace, H. M. (2019). Guidance on the use of the Threshold of Toxicological Concern approach in food safety assessment. EFSA Journal, 17(6), e05708. https://doi.org/10.2903/j.efsa.2019.5708
− Das, A., Das, A., &Banik, B. K. (2021). Influence of dipole moments on the medicinal activities of diverse organic compounds. Journal of the Indian Chemical Society, 98(2), 100005. https://doi.org/10.1016/j.jics.2021.100005
− Effects of chlorpromazine drug on DPPC lipid: Density functional theory study: International Journal of Environmental Analytical Chemistry: Vol 101 , No 12—Get Access. (n.d.). Retrieved March 29, 2025, from https://www.tandfonline.com/doi/full/10.1080/03067319.2019.1686497
− Garipelli, N., Reddy, B. M., & Av, J. (2009). Synthesis and Evaluation of Clozapine and its Related Compounds. International Journal of Pharmaceutical Sciences and Nanotechnology(IJPSN), 2(4), Article 4. https://doi.org/10.37285/ijpsn.2009.2.4.11
− Gaussian 09 Citation | Gaussian.com. (n.d.). Retrieved March 29, 2025, from https://gaussian.com/g09citation/
− Gómez-Jeria, J.-S., & Iberti-Arancibia, A. (2021). A DFT study of the relationships between electronic structure and dopamine D1 and D2 receptor affinity of a group of 11-(1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl)-5H-dibenzo[b,e][1,4]diazepines.
− Hannon, E., Dempster, E. L., Mansell, G., Burrage, J., Bass, N., Bohlken, M. M., Corvin, A., Curtis, C. J., Dempster, D., Di Forti, M., Dinan, T. G., Donohoe, G., Gaughran, F., Gill, M., Gillespie, A., Gunasinghe, C., Hulshoff, H. E., Hultman, C. M., Johansson, V., … Mill, J. (2021). DNA methylation meta-analysis reveals cellular alterations in psychosis and markers of treatment-resistant schizophrenia. eLife, 10, e58430. https://doi.org/10.7554/eLife.58430
− Hariharan, P. C., & and Pople, J. A. (1974). Accuracy of AH n equilibrium geometries by single determinant molecular orbital theory. Molecular Physics, 27(1), 209–214. https://doi.org/10.1080/00268977400100171
− Hirjak, D., Northoff, G., Taylor, S. F., & Wolf, R. C. (2021). GABAB receptor, clozapine, and catatonia-a complex triad. Molecular Psychiatry, 26(7), 2683–2684. https://doi.org/10.1038/s41380-020-00889-y
− Iwata, Y., Nakajima, S., Plitman, E., Truong, P., Bani-Fatemi, A., Caravaggio, F., Kim, J., Shah, P., Mar, W., Chavez, S., Remington, G., Gerretsen, P., De Luca, V., Sailasuta, N., & Graff-Guerrero, A. (2021). Glutathione Levels and Glutathione-Glutamate Correlation in Patients with Treatment-Resistant Schizophrenia. Schizophrenia Bulletin Open, 2(1), sgab006. https://doi.org/10.1093/schizbullopen/sgab006
− Karlsson, E., Larsson, L. E., & Nilsson, K. (1993). The effects of prophylactic dixyrazine on postoperative vomiting after two different anaesthetic methods for squint surgery in children. Acta Anaesthesiologica Scandinavica, 37(1), 45–48. https://doi.org/10.1111/j.1399-6576.1993.tb03596.x
− Kaya, S., & Putz, M. V. (2022). Atoms-In-Molecules’ Faces of Chemical Hardness by Conceptual Density Functional Theory. Molecules, 27(24), Article 24. https://doi.org/10.3390/molecules27248825
− Kim, D. D., Barr, A. M., Honer, W. G., &Procyshyn, R. M. (2018). Reversal of Dopamine Supersensitivity as a Mechanism of Action of Clozapine. Psychotherapy and Psychosomatics, 87(5), 306–307. https://doi.org/10.1159/000491700
− Liu, X., & De Haan, S. (2009). Chlorpromazine dose for people with schizophrenia. The Cochrane Database of Systematic Reviews, 2, CD007778. https://doi.org/10.1002/14651858.CD007778
− Martins, M., Dastidar, S. G., Fanning, S., Kristiansen, J. E., Molnar, J., Pagès, J.-M., Schelz, Z., Spengler, G., Viveiros, M., & Amaral, L. (2008). Potential role of non-antibiotics (helper compounds) in the treatment of multidrug-resistant Gram-negative infections: Mechanisms for their direct and indirect activities. International Journal of Antimicrobial Agents, 31(3), 198–208. https://doi.org/10.1016/j.ijantimicag.2007.10.025
− McRobb, F. M., Crosby, I. T., Yuriev, E., Lane, J. R., & Capuano, B. (2012). Homobivalent ligands of the atypical antipsychotic clozapine: Design, synthesis, and pharmacological evaluation. Journal of Medicinal Chemistry, 55(4), 1622–1634. https://doi.org/10.1021/jm201420s
− Molnár, J., Mándi, Y., & Király, J. (1976). Antibacterial effect of some phenothiazine compounds and R-factor elimination by chlorpromazine. Acta Microbiologica Academiae Scientiarum Hungaricae, 23(1), 45–54.
− Morak-Młodawska, B., & Jeleń, M. (2007). [New biological properties of neuroleptic phenothiazines]. Polski Merkuriusz Lekarski: Organ Polskiego Towarzystwa Lekarskiego, 23(138), 459–461.
− Park, B. K., Boobis, A., Clarke, S., Goldring, C. E. P., Jones, D., Kenna, J. G., Lambert, C., Laverty, H. G., Naisbitt, D. J., Nelson, S., Nicoll-Griffith, D. A., Obach, R. S., Routledge, P., Smith, D. A., Tweedie, D. J., Vermeulen, N., Williams, D. P., Wilson, I. D., & Baillie, T. A. (2011). Managing the challenge of chemically reactive metabolites in drug development. Nature Reviews. Drug Discovery, 10(4), 292–306. https://doi.org/10.1038/nrd3408
− Patlewicz, G., Jeliazkova, N., Safford, R. J., Worth, A. P., & Aleksiev, B. (2008). An evaluation of the implementation of the Cramer classification scheme in the Toxtree software. SAR and QSAR in Environmental Research, 19(5–6), 495–524. https://doi.org/10.1080/10629360802083871
− Robichon, K., Sondhauss, S., Jordan, T. W., Keyzers, R. A., Connor, B., & La Flamme, A. C. (2021). Localisation of clozapine during experimental autoimmune encephalomyelitis and its impact on dopamine and its receptors. Scientific Reports, 11(1), 2966. https://doi.org/10.1038/s41598-021-82667-6
− Smith, R. L., Maickel, R. P., & Brodie, B. B. (1963). ACTH-hypersecretion induced by phenothiazine tranquilizers. The Journal of Pharmacology and Experimental Therapeutics, 139, 185–190.
− Tavoloni, N., & Boyer, J. L. (1980). Relationship between hepatic metabolism of chlorpromazine and cholestatic effects in the isolated perfused rat liver. The Journal of Pharmacology and Experimental Therapeutics, 214(2), 269–274.
− Uetrecht, J. (2022). Idiosyncratic Drug Reactions: A 35-Year Chemical Research in Toxicology Perspective. Chemical Research in Toxicology, 35(10), 1649–1654. https://doi.org/10.1021/acs.chemrestox.2c00090
− Vinken, M. (2018). In vitro prediction of drug-induced cholestatic liver injury: A challenge for the toxicologist. Archives of Toxicology, 92(5), 1909–1912. https://doi.org/10.1007/s00204-018-2201-4
− Ww, G., M, S., & Wh, H. (1958). Termination of chlorpromazine with schizophrenic patients. The American Journal of Psychiatry, 115(5). https://doi.org/10.1176/ajp.115.5.443
− Xue, Z., Zhang, Y., Tao, J., Kang, Y., Chen, Z., & Xue, Y. (2016). Theoretical elucidation of the metabolic mechanisms of phenothiazine neuroleptic chlorpromazine catalyzed by cytochrome P450 isoenzyme 1A2. Theoretical Chemistry Accounts, 135(9), 218. https://doi.org/10.1007/s00214-016-1943-4