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Abstract
Inflammation plays a pivotal role in all stages of atherosclerosis and therefore targeting the key enzymes of this pathway may help in ameliorating the disease progression. The current study is aimed to identify small lead molecules as a promising inhibitor for the cyclooxygenase-2 (COX-2), a therapeutically important protein involved in the prostaglandin biosynthesis pathway and a key player in driving the inflammatory atherogenic progression. Herein, we have used extensive computational methods such as virtual screening, protein–ligand docking, molecular dynamics simulation and binding free energy analysis. Out of 2500 molecules, 1408 compounds have favourable drug-like properties. ZINC72348892 showed GOLD fitness score of 86.38 with COX-2 and established two hydrogen bonds with Phe519 and mostly hydrophobic interactions. The second lead ZINC72295579 showed GOLD fitness score of 84.07 with COX-2 and exhibited four hydrogen bonds with His90, Tyr356, Tyr386 and Ala528. Both the lead compounds exhibit high binding affinity for COX-2 compared with COX-1 isoenzyme. Further, the lead molecules showed a favourable Molecular mechanics Poisson–Boltzmann surface area (MM/PBSA) Gibbs binding free energy lower compared to the control. Van der Waal energy is the predominant component driving the interaction of the lead molecules with COX-2. Essential dynamics and entropy calculation further confirmed the structural rigidity and compactness of the protein upon binding of the lead molecules. Thus our findings suggest that ZINC72348892 and ZINC72295579 as promising lead molecules for inhibition of COX-2 and which would provide alternative chemotypes in the drug discovery pipeline for the treatment of cardiovascular diseases.
| Abbreviations | ||
| CVDs | = | Cardiovascular diseases |
| COX | = | Cyclooxygenase |
| MD | = | Molecular dynamics |
| MM/PBSA | = | Molecular mechanics Poisson–Boltzmann surface area |
| ROF | = | Rule of five |
| NVT | = | Number of particles, volume and temperature |
| NPT | = | Number of particles, pressure and temperature |
| RMSD | = | Root mean square deviation |
| RMSF | = | Root mean square fluctuation |
| SASA | = | Solvent accessible surface area |
| Rg | = | Radius of gyration |
| PCA | = | Principal component analysis |
| ED | = | Essential dynamics |
| NHBs | = | Number of hydrogen bonds |
Communicated by Ramaswamy H. Sarma
Acknowledgements
The authors gratefully acknowledge the high computing facility provided by the Computer Centre, NEHU.
Disclosure statement
The authors have no conflicts of interests to declare.
Additional information
Funding
Notes on contributors
Arun Bahadur Gurung
AB and ABG conceived of the presented idea. ABG carried out the molecular dynamics simulation study, participated in virtual screening and molecular docking analysis and drafted the manuscript. AL carried out virtual screening and molecular docking studies. AB investigated and supervised the findings of the studies. All authors read and approved the final manuscript.
Atanu Bhattacharjee
AB and ABG conceived of the presented idea. ABG carried out the molecular dynamics simulation study, participated in virtual screening and molecular docking analysis and drafted the manuscript. AL carried out virtual screening and molecular docking studies. AB investigated and supervised the findings of the studies. All authors read and approved the final manuscript.