QUANTUM MECHANICAL DESCRIPTORS OF NILOTINIB'S IMPURITIES
Objective: Mutagenic/genotoxic impurities in the clinically approved drugs have been a major concern for the pharmaceutical industry. Nilotinib (N), which is an approved drug of chronic leukemia, has a number of impurities (nilotinib impurity [NI]-3, NI-5, and NI-12). For drugs, either semi-empirical or quantum mechanical (QM) or topological molecular descriptors (MDs) have been popular for QSAR studies. However, details of MDs for impurities are yet to be established. Thus, the objective of the study has been to compute QM-based MDs for impurities of N and to compare them with that of approved drugs to identify MDs of the former in relation to their known genotoxic/mutagenic properties.
Methods: Impurities are optimized by B3LYP/6-311G (d,p) level of theory and ionization potential (IP), electron affinity (EA), and other MDs are determined. Further, non-linear optical (NLO) descriptors such as dipole moment (DM) and polarizability (Î±) are also determined.
Results: Impurities of N show much deviation of IP, EA, MD, Î±, and other properties from the reported mean values of approved drugs. Unlike NI-5 and NI-12, NI-3 shows increase in DM (~double) and Î± properties, which may point to its higher interactivity with cellular targets (like DNA/ RNA/protein), might be due to additional substituents, Ï€-conjugation, and planarity in its structure. The latter seems to be due to compensation of oppositely sensed dihedral properties of the structure of NI-3.
Conclusion: The study identifies QM-based differential MDs for impurities of N, which seems to have a relationship with their genotoxicity/ mutagenicity properties. Similar studies can be done for other such systems.
2. Larson RA, Hochhaus A, Hughes TP, Clark RE, Etienne G, Kim DW, et al. Nilotinib vs imatinib in patients with newly diagnosed philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: ENESTnd 3-year follow-up. Leukemia 2012;26:2197-203.
3. Beg S, Rizwan M, Sheikh AM, Hasnain MS, Anwer K, Kohli K, et al. Advancement in carbon nanotubes: Basics, biomedical applications and toxicity. J Pharm Pharmacol 2011;63:141-63.
4. Bwp DA, Chmp AB. European Medicines Agency Evaluation of Medicines for Human Use 2006.
5. McGovern T, Jacobson-Kram D. Regulation of genotoxic and carcinogenic impurities in drug substances and products. TrAC Trends Anal Chem 2006;25:790-5.
6. Guideline IH. Assessment and Control Of Dna Reactive (Mutagenic) Impurities In Pharmaceuticals To Limit Potential Carcinogenic RISK M7. InInternational Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human use (ICH): Geneva; 2014 Jun 5.
7. Matuszek AM, Reynisson J. Defining known drug space using DFT. Mol Inform 2016;35:46-53.
8. Schipper PR, Gritsenko OV, Van Gisbergen SJ, Baerends EJ. Molecular calculations of excitation energies and (hyper) polarizabilities with a statistical average of orbital model exchange-correlation potentials. J Chem Phys 2000;112:1344-52.
9. Balaji N, Sultana S. Sensitive determination of related substances in pioglitazone hydrochloride by hplc. Int J App Pharm 2017;9:34-41.
10. Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, et al. Gaussian 09 Revision a 02. Wallingford, CT: Gaussian Inc.; 2009. p. 200.
11. Dennington RD, Keith TA, Millam JM. Gauss View 5.0. Wallingford, CT: 2009.
12. Foresman JB, Frisch A. Exploring chemistry with electronic structure methods: A guide to using Gaussian. Pittsburgh, PA: Gaussian; 1996.
13. Ansary I, Das A, Gupta PS, Bandyopadhyay AK. Synthesis, molecular modeling of N-acyl benzoazetinones and their docking simulation on fungal modeled target. Synth Commun 2017;47:1375-86.
14. Kaduk JA, Zhong K, Gindhart AM, Blanton TN. Crystal structure of nilotinib, C 28 H 22 F 3 N 7 O. Powder Diffr 2015;30:270-7.
15. Weisberg E, Manley PW, Breitenstein W, BrÃ¼ggen J, Cowan-Jacob SW, Ray A, et al. Characterization of AMN107, a selective inhibitor of native and mutant bcr-abl. Cancer Cell 2005;7:129-41.
16. Raghunath M, Singh A, Viswanathan CL. Molecular descriptors and bioactivity scores of 6-substituted benzimidazole-2-carbamates as potential anticancer agents. World J Pharm Pharm Sci 2015;4:1438-4
17. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced drug delivery reviews 2012;64:4-17.
18. Ghose AK, Viswanadhan VN, Wendoloski JJ. A knowledge-based approach in designing combinatorial or medicinal chemistry libraries for drug discovery 1. A qualitative and quantitative characterization of known drug databases. J Comb Chem 1999;1:55-68.
19. Hurst GJ, Dupuis M, Clementi E. A binitio analytic polarizability, first and second hyperpolarizabilities of large conjugated organic molecules: Applications to polyenes C4H6 to C22H24. J Chem Phys 1988;89:385 95.
20. Zhou T, Huang D, Caflisch A. Quantum mechanical methods for drug design. Curr Top Med Chem 2010;10:33-45.
21. Krauth F, Dahse HM, RÃ¼ttinger HH, Frohberg P. Synthesis and characterization of novel 1,2,4-triazine derivatives with antiproliferative activity. Bioorg Med Chem 2010;18:1816-21.
22. Bhatt P, Deepthi S, Kumar CR, Jhaa AN. Facile synthesis, spectral studies, dft calculations and biological activities of novel ni (ii), cu (ii), and pd (ii) complexes of thiadiazole analogs. International Journal of Pharmacy and Pharmaceutical Sciences 2017;9(4);185-92.
23. Pearson RG. The electronic chemical potential and chemical hardness. J Mol Struct THEOCHEM 1992;255:261-70.
24. Woon DE, Dunning Jr. TH. Gaussian basis sets for use in correlated molecular calculations. IV. Calculation of static electrical response properties. J Chem Phys 1994;100:2975-88.
25. Hao MH, Haq O, Muegge I. Torsion angle preference and energetics of small-molecule ligands bound to proteins. J Chem Inf Model 2007;47:2242-52.
26. Ma J, Karplus M. Ligand-induced conformational changes in ras p21: A normal mode and energy minimization analysis. J Mol Biol 1997;274:114-31.
27. Kompella A, Rao AK, Rachakonda S, Gampa VK, Nannapaneni VC. Inventors; Natco Pharma Ltd, Assignee. Process for the Preparation of Nilotinib. United States Patent US 9,061,028. 2015 Jun 23.
28. Stiehler J, Hinze J. Calculation of static polarizabilities and hyperpolarizabilities for the atoms He through Kr with a numerical RHF method. J Phys B At Mol Opt Phys 1995;28:4055.
29. Chen L, Lu J, Huang T, Cai YD. A computational method for the identification of candidate drugs for non-small cell lung cancer. PLoS One 2017;12:e0183411.
30. Aihara JI. Reduced HOMO-LUMO gap as an index of kinetic stability for polycyclic aromatic hydrocarbons. J Phys Chem A 1999;103:7487 95.
31. Obot IB, Obi-Egbedi NO, Umoren SA. Antifungal drugs as corrosion inhibitors for aluminium in 0.1 M HCl. Corrosion Science 2009;51(8):1868-75.
32. Ghanadzadeh A, Ghanadzadeh H, Ghasmi G. On the molecular structure and aggregative properties of Sudan dyes in the anisotropic host. J Mol Liq 2000;88:299-308.
33. Zhan CG, Nichols JA, Dixon DA. Ionization potential, electron affinity, electronegativity, hardness, and electron excitation energy: Molecular properties from density functional theory orbital energies. J Phys Chem A 2003;107:4184-95.
34. Xue Y, Li ZR, Yap CW, Sun LZ, Chen X, Chen YZ, et al. Effect of molecular descriptor feature selection in support vector machine classification of pharmacokinetic and toxicological properties of chemical agents. J Chem Inf Comput Sci 2004;44:1630-8.
35. Harris PG, Baker CA, Green K, Iaydjiev P, Ivanov S, May DJ, et al. New experimental limit on the electric dipole moment of the neutron. Phys Rev Lett 1999;82:904.
36. Lim IS, Pernpointner M, Seth M, Laerdahl JK, Schwerdtfeger P, Neogrady P, et al. Relativistic coupled-cluster static dipole polarizabilities of the alkali metals from Li to element 119. Phys Rev A 1999;60:2822.
37. Hansch C, Steinmetz WE, Leo AJ, Mekapati SB, Kurup A, Hoekman D, et al. On the role of polarizability in chemical-biological interactions. J Chem Inf Comput Sci 2003;43:120-5.
38. Boger DL, Desharnais J, Capps K. Solution-phase combinatorial libraries: Modulating cellular signaling by targeting protein-protein or protein-DNA interactions. Angew Chem Int Ed Engl 2003;42:4138-76.
39. Lee JY, Kim KS, Mhin BJ. Intramolecular charge transfer of Ï€-conjugated push-pull systems in terms of polarizability and electronegativity. J Chem Phys 2001;115:9484-9.
40. Gresh N, Cisneros GA, Darden TA, Piquemal JP. Anisotropic, polarizable molecular mechanics studies of inter- and intramolecular interactions and ligand-macromolecule complexes. A Bottom-up strategy. J Chem Theory Comput 2007;3:1960-86.
41. Ghanadzadeh A, Zakerhamidi MS, Tajalli H. Electric linear dichroism study of some Sudan dyes using electro-optic and spectroscopic methods. J Mol Liq 2004;109:143-8.
42. Lazzeretti P. Assessment of aromaticity via molecular response properties. Phys Chem Chem Phys 2004;6:217-23.