Molecular Dynamics Studies on COX-2 Protein-tyrosine Analogue Complex and Ligand-based Computational Analysis of Halo-substituted Tyrosine Analogues

Background: The quest for new drug entities and novel structural fragments with applications in therapeutic areas is always at the core of medicinal chemistry. Methods: As part of our efforts to develop novel selective cyclooxygenase-2 (COX-2) inhibitors containing tyrosine scaffold. The objective of this study was to identify potent COX-2 inhibitors by dynamic simulation, pharmacophore and 3D-QSAR methodologies. Dynamics simulation was performed for COX-2/tyrosine derivatives complex to characterise structure validation and binding stability. Certainly, Arg120 and Tyr355 residue of COX-2 protein formed a constant interaction with tyrosine inhibitor throughout the dynamic simulation phase. A four-point pharmacophore with one hydrogen bond acceptor, two hydrophobic and one aromatic ring was developed using the HypoGen algorithm. The generated, statistically significant pharmacophore model, Hypo 1 with a correlation coefficient of r2, 0.941, root mean square deviation, 1.15 and total cost value of 96.85. Results: The QSAR results exhibited good internal (r2, 0.992) and external predictions (r2pred, 0.814). The results of this study concluded the COX-2 docked complex was stable and interactive like experimental protein structure. Also, it offered vital chemical features with geometric constraints responsible for the inhibition of the selective COX-2 enzyme by tyrosine derivatives. Conclusion: In principle, this work offers significant structural understandings to design and develop novel COX-2 inhibitors.