Computational Quantum Chemical Study, Drug-Likeness and In Silico Cytotoxicity Evaluation of Some Steroidal Anti-Inflammatory Drugs
Abstract
This paper contains a theoretical study of ten Anti-inflammatory steroids (AIS) on the understanding of the relationship between the structure and activity of the drug, the pharmacokinetic parameters responsible for bioavailability and bioactivity and finally the toxicity evaluation. DFT calculations with B3LYP/6-31G (d, p) level have been used to analyze the electronic and geometric characteristics deduced for the stable structure of the compounds. Moreover, using the Frontier Molecular orbital (FMO) energies, MEP surface visualizations and the density-based descriptors such as chemical potential (µ), electronegativity (χ), hardness (η) and softness (σ), the chemical stability were determined. Furthermore, in silico, studies showed that Lipinski rules are applied, which means that these (AIS) are expected to have a high probability of good oral bioavailability. On the other side, the bioinformatic Osiris/Molinspiration analyses of the relative cytotoxicity of these derivatives are reported in comparison to Cortisol. In fact, it has been showed that almost of these compounds are non-toxics except for Mometasone that presents a great risk of tumorigenicity during reproduction with a slightly mutagenic structure due to the two chloride atoms. from all results obtained, we can conclude that fluticasone has the best physico-chemical properties which explains its high efficiency.
Keywords: Anti-inflammatory steroids, DFT, Lipinski rules, Tumorigenicity.
Keywords:
Anti-inflammatory steroids, DFT, Lipinski rules, Tumorigenicity
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References
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2. Wilckens T. Further thoughts on the immunomodulatory role of glucocorticoids: comment on the article by Buttgereit et al. Arthritis & Rheumatism: Official Journal of the American College of Rheumatology. Wiley Online Library; 1999; 42:393–395.
3. Coutinho AE, Chapman KE. The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights. Mol Cell Endocrinol. 2011; 335:2–13.
4. Adcock IM. Molecular mechanisms of glucocorticosteroid actions. Pulmonary pharmacology & therapeutics. Elsevier; 2000; 13:115–126.
5. Barnes PJ. Anti-inflammatory actions of glucocorticoids: molecular mechanisms. Clinical science. Portland Press Ltd.; 1998; 94:557–572.
6. Barnes PJ. Molecular mechanisms of corticosteroids in all_ergic diseases. Allergy. Wiley Online Library; 2001; 56:928–936.
7. Weinstein RS. Glucocorticoid-induced osteonecrosis. Endocrine. 2012; 41:183–90.
8. Kerassa A, Belaidi S, Harkati D, Lanez T, Prasad O, Sinha L. Investigations on Molecular Structure, Electronic Properties, NLO Properties and Comparison of Drug-Likeness of Triazolothiadiazole Derivatives by Quantum Methods and QSAR Analysis. Reviews in Theoretical Science. American Scientific Publishers; 2016; 4:85–96.
9. Dearden JC. The history and development of quantitative structure-activity relationships (QSARs). Oncology: breakthroughs in research and practice. IGI Global; 2017. page 67–117.
10. Tropsha A. Best practices for QSAR model development, validation, and exploitation. Molecular informatics. Wiley Online Library; 2010; 29:476–488.
11. Raghavachari K. Perspective on “Density functional thermochemistry. III. The role of exact exchange.” Theoretical Chemistry Accounts. Springer; 2000; 103:361–363.
12. Civalleri B, Wilson Z, Valenzano L, Ugliengo P. B3LYP augmented with an empirical dispersion term (B3LYP-D*) as applied to molecular crystals. 2008;
13. Dennington RD, Keith TA, Millam JM. GaussView 5.0, Gaussian. Inc, Wallingford. 2008;
14. Robles J, Bartolotti LJ. Electronegativities, electron affinities, ionization potentials, and hardnesses of the elements within spin polarized density functional theory. Journal of the American Chemical Society. ACS Publications; 1984; 106:3723–3727.
15. Elsharkawy ER, Almalki F, Ben Hadda T, Rastija V, Lafridi H, Zgou H. DFT calculations and POM analyses of cytotoxicity of some flavonoids from aerial parts of Cupressus sempervirens: Docking and identification of pharmacophore sites. Bioorganic Chemistry. 2020; 100:103850.
16. Kim B-G, Ma X, Chen C, Ie Y, Coir EW, Hashemi H, et al. Energy level modulation of HOMO, LUMO, and band-gap in conjugated polymers for organic photovoltaic applications. Advanced Functional Materials. Wiley Online Library; 2013; 23:439–445.
17. Politzer P, Laurence PR, Jayasuriya K. Molecular electrostatic potentials: an effective tool for the elucidation of biochemical phenomena. Environmental health perspectives. 1985; 61:191–202.
18. Benzon KB, Varghese HT, Panicker CY, Pradhan K, Tiwary BK, Nanda AK, et al. Spectroscopic and theoretical characterization of 2-(4-methoxyphenyl)-4,5-dimethyl-1H-imidazole 3-oxide. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy. 2015; 151:965–79.
19. Barim E, Akman F. Synthesis, characterization and spectroscopic investigation of N-(2-acetylbenzofuran-3-yl)acrylamide monomer: Molecular structure, HOMO–LUMO study, TD-DFT and MEP analysis. Journal of Molecular Structure. 2019; 1195:506–13.
20. Mehri M, Chafai N, Ouksel L, Benbouguerra K, Hellal A, Chafaa S. Synthesis, electrochemical and classical evaluation of the antioxidant activity of three α-aminophosphonic acids: Experimental and theoretical investigation. Journal of Molecular Structure. 2018; 1171:179–89.
21. Rachedi KO, Ouk T-S, Bahadi R, Bouzina A, Djouad S-E, Bechlem K, et al. Synthesis, DFT and POM analyses of cytotoxicity activity of α-amidophosphonates derivatives: Identification of potential antiviral O,O-pharmacophore site. Journal of Molecular Structure. 2019; 1197:196–203.
22. Remko M. Molecular structure, lipophilicity, solubility, absorption, and polar surface area of novel anticoagulant agents. Journal of Molecular Structure: THEOCHEM. 2009; 916:76–85.
23. Abraham MH, Ibrahim A, Zissimos AM, Zhao YH, Comer J, Reynolds DP. Application of hydrogen bonding calculations in property based drug design. Drug Discovery Today. 2002; 7:1056–63.
24. Deconinck E, Ates H, Callebaut N, Van Gyseghem E, Vander Heyden Y. Evaluation of chromatographic descriptors for the prediction of gastro-intestinal absorption of drugs. Journal of Chromatography A. 2007; 1138:190–202.
25. Daina A, Michielin O, Zoete V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Scientific reports. Nature Publishing Group; 2017; 7:42717.
26. Edmondson SD, Yang B, Fallan C. Proteolysis targeting chimeras (PROTACs) in ‘beyond rule-of-five’ chemical space: Recent progress and future challenges. Bioorganic & Medicinal Chemistry Letters. 2019; 29:1555–64.
27. Szakács G, Váradi A, Özvegy-Laczka C, Sarkadi B. The role of ABC transporters in drug absorption, distribution, metabolism, excretion and toxicity (ADME–Tox). Drug Discovery Today. 2008; 13:379–93.
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Bououden W, Benguerba Y. Computational Quantum Chemical Study, Drug-Likeness and In Silico Cytotoxicity Evaluation of Some Steroidal Anti-Inflammatory Drugs. JDDT [Internet]. 15Jun.2020 [cited 2Jul.2020];10(3-s):68-4. Available from: http://jddtonline.info/index.php/jddt/article/view/4165
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