Abstract
Background
Ketorolac (KTR) is used as an analgesic drug with an efficacy close to that of the opioid family. It is mainly used for the short term treatment of post-operative pain. It can inhibit the prostaglandin synthesis by blocking cyclooxygenase (COX).
Methods
In this investigation, the inherent stability and biochemical interaction of Ketorolac (KTR) and its degradation products have been studiedon the basis of quantum mechanical approaches. Density functional theory (DFT) with B3LYP/ 6-31G (d) has been employed to optimize the structures. Thermodynamic properties, frontier molecular orbital features, dipole moment, electrostatic potential, equilibrium geometry, vibrational frequencies and atomic partial charges of these optimized structureswere investigated. Molecular docking has been performed against prostaglandin H2 (PGH2) synthase protein 5F19 to search the binding affinity and mode(s). ADMET prediction has performed to evaluate the absorption, metabolism and carcinogenic properties.
Results
The equilibrium geometry calculations support the optimized structures. Thermodynamic results disclosed the thermal stability of all structures. From molecular orbital data, all the degradents are chemically more reactive than parent drug (except K3). However, the substitution of carboxymethyl radicalin K4 improved the physicochemical properties and binding affinity. ADMET calculations predict the improved pharmacokinetic and non-carcinogenic properties of all degradents.
Conclusion
Based on physicochemical, molecular docking, and ADMET calculation, this study can be helpful to understand the biochemical activities of Ketorolac and its degradents and to design a potent analgesic drug.
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Abbreviations
- KTR:
-
Ketorolac
- DFT:
-
Density functional theory
- HOMO:
-
Highest occupied molecular orbital
- LUMO:
-
Lowest unoccupied molecular orbital
- MEP:
-
Molecular electrostatic potential
- ADMET:
-
Absorption, distribution, metabolism, excretion, toxicity
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Acknowledgements
Authors are thankful to Dr. Mohammad A. Halim (COE, The Red –Green Research Centre, Dhaka, Bangladesh) for his valuable suggestion.
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Mohammad Nasir Uddin (MNU) and Moniruzzaman (M) conceived the idea and prepared the manuscript. M performed all quantum chemical calculations and data collection. All authors read and approved the manuscript.
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Uzzaman, M., Uddin, M.N. Optimization of structures, biochemical properties of ketorolac and its degradation products based on computational studies. DARU J Pharm Sci 27, 71–82 (2019). https://doi.org/10.1007/s40199-019-00243-w
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DOI: https://doi.org/10.1007/s40199-019-00243-w