A Detailed Study of Solvent-Ligand Interactions and in Silico Biological Activity Predictions on Hydroxychloroquine

Abstract

In this study, the effects of solvent environment changes, which are of critical importance in drug production processes, on the geometric structure and physicochemical parameters of the Hydroxychloroquine (HQC) molecule were investigated. For this purpose, optimized molecule structures were obtained using Density Functional Theory in vacuum and solvent environments. Based on the optimized structures, the molecule's thermochemical properties, atomic charges, and chemical reactivity data were calculated in vacuum and solvent environments. Moreover, the molecule's molecular electrostatic potential map and HOMO-LUMO contour maps were drawn. Vibrational frequencies, intensities, and assignments in solvent environments were determined. The characteristics of the hydrogen bonding interactions established between solvent molecules and HQC were determined in detail. ADME, toxicity, and drug-likeness predictions of the molecule were made. The study results showed that while the structural, chemical, and physical properties of the HQC molecule were severely affected when transferred to the solvent environment, they were less affected by the changes between solvent environments. In addition, very strong h-bond interactions are established between the solvent molecules and HQC.

Keywords

• Solvent Effects
• In silico Predictions
• ADME-T
• Density Functional Theory

References

1. Acerce, H. C., Hasgül, B., Karaman, S. (2022). COVID-19 Hastalığı ve Üst Solunum Yolu Enfeksiyonu Tanısı Alan Hastaların Hemogram Parametrelerininin Kıyaslanması. Gaziosmanpaşa Üniversitesi Tıp Fakültesi Dergisi, 3, 156
2. Altalhi, T.A., Alswat, K., Alsanie, W. F., Ibrahim, M. M., Aldalbahi, A. A., El-Sheshtawy H. S., (2021). Chloroquine and hydroxychloroquine inhibitors for COVID-19 sialic acid cellular receptor: Structure, Hirschfeld atomic charge analysis and solvent effect. Journal of Molecular Structure, 1228, 129459.
3. Amin, M., Abbas, G. (2021). Docking study of chloroquine and hydroxychloroquine interaction with RNA binding domain of nucleocapsid phospho-protein – an in silico insight into the comparative efficacy of repurposing antiviral drugs. Journal of Biomolecular Structure and Dynamics, 39, 4243.
4. Anonymous (2019)."Absolute lethal dose (LD100)". IUPAC Gold Book. International Union of Pure and Applied Chemistry. Archived from the original on 2019-07-01. Retrieved.
5. Anonymous (2021) "What is a LD50 and LC50?". OSH Answers Fact Sheets. Canadian Centre for Occupational Health and Safety.
6. Bilkan, M. T. (2017). Structural and spectroscopic studies on dimerization and solvent-ligand complexes of Theobromine. Journal of Molecular Liquids, 238, 523. Bilkan, M.T. (2019). Quantum chemical studies on solvent effects, ligand–water complexes and dimer structure of 2, 2ʹ-dipyridylamine. Physics and Chemistry of Liquids, 57, 100. Boys, S.F., Bernardi, F. (1970). The calculation of small molecular interactions by the differences of separate total energies. Some procedures with reduced errors. Molecular Physics, 19, 553.
7. Butina, D., Segall, M. D., Frankcombe, K. (2002). Predicting ADME properties in silico: methods and models. Drug Discovery Today, 7, 83.
8. Cetin, A., Donmez, A., Dalar, A., & Bildirici, I. (2023). Amino acid and Dicyclohexylurea Linked Pyrazole Analogues: Synthesis, In Silico and In Vitro Studies. ChemistrySelect, 8(6), e202204926.

9. Cetin, A., Donmez, A., Dalar, A., & Bildirici, I. (2023). Tetra-substituted pyrazole analogues: synthesis, molecular docking, ADMET prediction, antioxidant and pancreatic lipase inhibitory activities. Medicinal Chemistry Research, 32(1), 189-204.
10. Chafai, N., Benbouguerra, K., Chafaa, S., Hellal, A. (2022). Quantum Chemical Study of Hydroxychloroquine and Chloroquine Drugs Used as a Treatment of COVID-19. Iranian Journal of Chemistry and Chemical Engineering, 41, 27.
11. Christopher, A. L. (2004). Lead- and drug-like compounds: the rule-of-five revolution. Drug Discovery Today Technologies 1, 337.
12. Dege, N., Gökçe, H., Doğan, O. E., Alpaslan, G., Ağar, T., Muthu, S., Sert, Y. (2022). Quantum computational, spectroscopic investigations on N-(2-((2-chloro-4,5-dicyanophenyl)amino) ethyl)-4-methylbenzenesulfonamide by DFT/TD-DFT with different solvents, molecular docking and drug-likeness researches. Colloids and Surfaces A, 638, 128311.
13. Dennington, R.D., Keith, T.A., Millam, J.M. (2008). GaussView 5, Gaussian, Inc.
14. Ejuh, G.W., Fonkem, C., Tadjouteu Assatse, Y., Yossa Kamsi, R.A., Tchangnwa Nya, Ndukum, L.P., Ndjaka, J.M.B., (2020), Study of the structural, chemical descriptors and optoelectronic properties of the drugs Hydroxychloroquine and Azithromycin. Heliyon, 6, e04647.
15. Fox, R. I. (1993) Mechanism of action of hydroxychloroquine as an antirheumatic drug. Seminars in Arthritis and Rheumatism, 23, 82.
16. Frisch, M. J. et al., (2009). Gaussian 09, Revision B.01, Gaussian Inc., C.T. Wallingford.
17. Hasgül, B., Karaman, S., Çatak, A. İ. (2022). COVID-19 Hastalığı Sonrası Aşılanmamış Hastalarda Demografik Özellikler, Antikor Seviyeleri ve Akciğer Tutulumlarının Değerlendirilmesi. Gaziosmanpaşa Üniversitesi Tıp Fakültesi Dergisi, 1, 1.
18. Gangadharan, R. P., Krishnan, S. S. (2014). Natural Bond Orbital (NBO) population analysis of 1-azanapthalene-8-ol. Acta Physica Polonica A, 125.1, 18. Ghiandoni, G. M., Caldeweyher, E. (2023). Fast calculation of hydrogen‑bond strengths and free energy of hydration of small molecules. Scientific Reports, 13, 1.
19. "Hydroxychloroquine Sulfate Monograph for Professionals". (20 March 2020), The American Society of Health-System Pharmacists.
20. Jamróz, M.H. (2004). Vibrational Energy Distribution Analysis. VEDA 4, Warsaw.
21. Janssen, J., Saluja, S. S. (2015). How much did you take? Reviewing acetaminophen toxicity. Canadian Family Physician. 61, 347.
22. Kawsar, S.M.A., Hosen, M.A., Fujii, Y., Ozeki, Y. (2020). Thermochemical, DFT, Molecular Docking and Pharmacokinetic Studies of Methyl β-D-galactopyranoside Esters. Journal of Computational Chemisitry, 4, 452.
23. Korkmaz, A., Cetin, A., Kaya, E., Erdoğan, E. (2018). Novel polySchiff base containing naphthyl: synthesis, characterization, optical properties and surface morphology. Journal of Polymer Research, 25, 1-8.
24. Lea, T. (2015). Caco-2 Cell Line, The Impact of Food Bioactives on Health in Vitro and Ex Vivo Models. Springer, Cham, Chapter 10.
25. Lien, E. J., Guo, Z., Li, R. L., Su, C. T. (1982). Use of dipole moment as a parameter in drug-receptor interaction and quantitative structure-activity relationship studies. Journal of Pharmacological Sciences, 71, 641.
26. Liu, X. Y., Xu, Y. N., Wang, H. C., Cao, J. W., Qin, X. L., Zhang, P. (2021). First-principles DFT investigations of the vibrational spectra of chloro-quine and hydroxychloroquine. Journal of Physics Communications, 5 105009.
27. Ma, X.L., Chen, C., Yang, J. (2005). Predictive model of blood-brain barrier penetration of organic compounds. Acta Pharmacologica Sinica, 26, 500.
28. Noureddine, O., Issaoui, N., Medimagh, M., Al-Dossary, O., Marouani, H. (2021). Quantum chemical studies on molecular structure, AIM, ELF, RDG and antiviral activities of hybrid hydroxychloroquine in the treatment of COVID-19: Molecular docking and DFT calculations. Journal of King Saud University - Engineering Sciences, 33, 101334.
29. Omer, R. A., Ahmed, L. O., Koparir, M., Koparir, P. (2020). Theoretical analysis of the reactivity of chloroquine and hydroxychloroquine. Indian Journal of Chemistry, 59A, 1828.
30. Parlak, C., Alver, Ö., Ouma, C.N.M., Rhyman, L., Ramasami, P. (2022). Interaction between favipiravir and hydroxychloroquine and their combined drug assessment: in silico investigations. Chemicke Zvesti, 76, 1471. Parr, R.G., Szentpa´ly, L.V., Liu, S. (1999). Computational Analysis of Theacrine, a Purported Nootropic and Energy-Enhancing Nutritional Supplement. Journal of American Chemical Society, 121, 1922.
31. Pearson, R. G. (1986). Absolute electronegativity and hardness correlated with molecular orbital theory. Proceedings of the National Academy of Sciences, 83(22), 8440-8441.
32. PreADMET, (2022).
33. ProTox-II- Prediction of Toxicity of Chemicals, (2022).
34. Seyma Sevincli, Z., Bildirici, N., Cetin, A., & Bildirici, I. (2023). GABA–AT Inhibitors: Design, Synthesis, Pharmacological Characterization, Molecular Docking and ADMET Studies. ChemistrySelect, 8(35), e202302683.
35. Singh, J., Malik, D., Raina, A. (2021). Molecular docking analysis of azithromycin and hydroxychloroquine with spike surface glycoprotein of SARS-CoV-2. Bioinformation. 17, 11.
36. Üstün, E., Demir, S., Coşkun, F., Kaloğlu, M., Şahin, O., Büyükgüngör, O., & Özdemir, İ. (2016). A theoretical insight for solvent effect on myoglobin assay of W (CO) 4L2 type novel complexes with DFT/TDDFT. Journal of Molecular Structure, 1123, 433-440.
37. Üstün, E., & Mehel, A. K. (2018). Solvent Effects on Frontier Orbitals and Electronic Transitions of Manganese Carbonyl Complexes: A DFT/TDDFT Study. Orbital: The Electronic Journal of Chemistry, 509-514.
38. WHO Coronavirus (COVID-19) Dashboard//https://covid19.who.int/table.
39. WHO model list of essential medicines: 21st list 2019. World Health Organization. hdl:10665/325771 (2019).
40. Yoon, E., Babar, A., Choudhary, M., Kutner, M., Pyrsopoulos, N. (2016). Acetaminophen-Induced Hepatotoxicity: a Comprehensive Update. Journal of Clinical and Translational Hepatology, 28, 131.
41. Yurdakul, Ş., Bilkan, M.T. (2015). Spectroscopic and structural properties of 2, 2′-dipyridylamine and its palladium and platinum complexes. Optics and Spectroscopy, 119, 603.
42. Zheng, Y. Z., Zhou, Y., Liang, Q., Chen, D. F., Guo, R., Lai, R. C. (2016). Hydrogen-bonding Interactions between Apigenin and Ethanol/Water: A Theoretical Study. Scientific Reports. 6, 34647.