Klormetiyazol’ün Partisyon Katsayısının Tahmin Edilmesi İçin Hesaplamalı Yöntemlerin Kıyaslama Çalışması

Abstract

Bu çalışma, kuantum kimyasal hesaplama teknikleri kullanılarak Klormetiazol molekülünün lipofiliklik tahmini, HOMO-LUMO analizi ve elektrostatik yüzey özelliklerinin değerlendirmelerini içermektedir. Tüm geometrik optimizasyonlar, enerji ve frekans hesaplamaları, Hartree-Fock (HF) yöntemi ve iki farklı Yoğunluk Fonksiyonel Teori (YFT) fonksiyoneli B3LYP ve B3PW91 seçilerek altı farklı temel set ile gerçekleştirilmiştir. Çözücü etkisini araştırmak ve ayrıca bölme katsayılarını tahmin etmeye yardımcı olan Gibbs solvasyon serbest enerjilerini elde etmek için tüm hesaplamalar su ve n-oktanol fazları için SMD solvasyon modeli kullanılarak tekrarlanmıştır. Sonuç olarak, uygulanan teorik yöntemler arasında deneysel logP değeri ile en iyi uyum HF/6-31G(d,p) yöntemi ile elde edilmiştir. Ayrıca hesaplamalı yöntemlerin tahmin performansının HF> B3LYP> B3PW91 sırasıyla azaldığı sonucuna varılmıştır.

Keywords

• Klormetiyazol
• DFT
• HOMO-LUMO
• Lipofiliklik

Benchmark Study of Computational Methods for Predicting Partition Coefficient of Chlormethiazole

Abstract

The present study contains the evaluations of lipophilicity estimation, HOMO-LUMO analysis, and electrostatic surface properties of Chlormethiazole molecule by using quantum chemical calculation techniques. All geometrical optimizations, energy and frequency calculations were carried out with six different basis sets by choosing the Hartree-Fock (HF) method and two different Density Functional Theory (DFT) functionals B3LYP and B3PW91. All calculations were repeated for the water and n-octanol phases by using SMD solvation model in order to investigate the solvent effect and also to obtain the Gibbs free energies of solvation that help to estimate partition coefficients. As a result, among the applied theoretical methods, the best agreement with the experimental logP value was obtained with the HF/6-31G(d,p) method. Also, it is concluded that the forecast performance of the computational methods decreases in the following order: HF> B3LYP> B3PW91.

Keywords

• Chlormethiazole
• DFT
• HOMO-LUMO
• Lipophilicity

References

1. [1]. Van De Waterbeemd, H., Gifford, E., ADMET in silico modelling:towards prediction paradise?, Nat. Rev. Drug Discov., 2003, 2(3), 192-204.
2. [2]. Van de Waterbeemd, H., Smith, D. A., Jones, B. C., Lipophilicity in PK design: methyl, ethyl, futile, J. Comput. Aided Mol. Des., 2001, 15, 273–286.
3. [3]. Fong, C. W., Statins in therapy: understanding their hydrophilicity, lipophilicity, binding to 3-hydroxy-3-methylglutaryl-CoA reductase, ability to cross the blood brain barrier and metabolic stability based on electrostatic molecular orbital studies, Eur. J. Med. Chem., 2014, 85, 661-674.
4. [4]. Hansch, C., Björkroth, J. P., Leo, A., Hydrophobicity and central nervous system agents: on the principle of minimal hydrophobicity in drug design. J. Pharm. Sci. 1987, 76(9), 663-687.
5. [5]. Hansch, C., Fujita, T., p-σ-π Analysis. A method for the correlation of biological activity and chemical structure. J. Am. Chem. Soc., 1964, 86(8), 1616-1626.
6. [6]. Bergström, C., Charman, W. and Porter, C., Computational prediction of formulation strategies for beyond rule-of-5 compounds. Adv. Drug Deliv. Rev., 2016, 101, 6-21.
7. [7]. Bohnert, T., Prakash, C., ADME profiling in drug discovery and development: an overview. Encyclopedia of Drug Metabolism and Interactions, 2012, 1-35.
8. [8]. Chun, M. S., Shen, J. L., and Joo, C. T., Recent advances in computer-aided drug design. Briefings in Bioinformatics, 2009, 10(5), 579-591.

9. [9]. Mayer, J. M., van de Waterbeemd, H., Development of quantitative structure-pharmacokinetic relationships. Environ. Health Perspect., 1985, 61, 295-306.
10. [10]. Gupta, S. P., QSAR studies on drug acting at the central nervous system. Chem. Rev., 1989, 89, 1765-1800.
11. [11]. Van de Waterbeemd, H., Rose, S., ‘In The Practice of Medicinal Chemistry’. San Diego: Academic Press, (2003).
12. [12]. Wilby, M. J., Hutchinson, P. J., The pharmacology of chlormethiazole: a potential neuroprotective agent. CNS Drug Reviews, 2004, 10(4), 281–294.
13. [13]. Majumdar, S. K., Chlormethiazole: current status in the treatment of the acute ethanol withdrawal syndrome. Drug and Alcohol Dependence, 1991, 27(3), 201-207.
14. [14]. Morgan, M. Y., The management of alcohol withdrawal using chlormethiazole. Alcohol & Alcoholism, 1995, 30(6), 771-774.
15. [15]. Frisch, M. J., Trucks, G. W., Schlegel, H. B., Scuseria, G. E., Robb, M. A., Cheeseman, J. R., et al., 2009, Gaussian 09, Revision D.01, Gaussian, Inc., Wallingford, CT.
16. [16]. Dennington, R., Keith, T., Millam, J., 2009, Gauss View, Version 5., Semichem Inc., Shawnee Mission, KS.
17. [17]. Becke, A. D., A new mixing of Hartree–Fock and local density functional theories. J. Chem. Phys, 1993, 98, 1372–1377.
18. [18]. Lee, C., Yang, W., Parr, R. G., Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density. Physical Review B, 1988, 37, 785–789.
19. [19]. Becke, A. D., Density‐functional thermochemistry. III. The role of exact exchange. J. Chem. Phys, 1993, 98, 5648–5652.
20. [20]. Perdew, J. P., Chevary, J. A., Vosko, S. H., Jackson, K. A., Pederson, M. R., Singh, D. J., C. Fiolhais, C., Atoms, molecules, solids, and surfaces: applications of the generalized gradient approximation for exchange and correlation. Phys. Rev. B Condens. Matter, 1992, 46(11), 6671-6687.
21. [21]. Port, A., Bordas, M., Enrech, R., Pascual, R., Rosés, M., Ràfols, C. et al., Critical comparison of shake-flask, potentiometric and chromatographic methods for lipophilicity evaluation (logPo/w) of neutral, acidic, basic, amphoteric, and zwitterionic drugs. Eur J Pharm Sci, 2018, 122, 331– 340.
22. [22]. Devoe, H., Miller, M. M., Wasik, S. P., Generator columns and high-pressure liquid chromatography for determining aqueous solubilities and octanol-water partition coefficients of hydrophobic substances. J Res Natl Inst Stand Technol, 1981, 86(4), 361-366.
23. [23]. Xiang, Q., Shan, G., Wu, W., Jin, H., Zhu, L., Measuring logKow coefficients of neutral species of perfluoroalkyl carboxylic acids using reversed-phase high-performance liquid chromatography. Environmental Pollution, 2018, 242, 1283–1290.
24. [24]. Garrido, N. M., Queimada, A. J., Jorge, M., Macedo, E. A., Ioannis G. Economou, I. G., 1-Octanol/water partition coefficients of n-alkanes from molecular simulations of absolute solvation free energies. J. Chem. Theory Comput., 2009, 5, 2436-2446.
25. [25]. Marenich, A. V., Cramer, C. J., Truhlar, D. G., Universal solvation model based on solute electron density and on a continuum model of the solvent defined by the bulk dielectric constant and atomic surface tensions. J. Phys. Chem. B, 2009, 113, 6378–6396.
26. [26]. Serdaroğlu, G., Şahin, N., Üstün, E., Tahir, M. N., Arıcı, C., Gürbüz, N., Özdemir, İ., PEPPSI type complexes: synthesis, x-ray structures, spectral studies, molecular docking and theoretical investigations. Polyhedron, 2021, 204, 115281.
27. [27]. Murray, J. S., P. Politzer, P., The electrostatic potential: an overview. Wiley Interdiscip. Rev. Comput. Mol. Sci. 2011, 1, 153-322.