Investigation of Inhibitory and Anti-inflammatory Effect of New Imidazole Derivatives on Cox-۲

Cyclooxygenase enzyme is a transmembrane integral homodimer protein. COX-۱ and COX-۲ are two main isoforms that have been identified. Both isoforms are bifunctional enzymes. Each subunit consists of three domains: the epidermal growth factor domain, membrane binding domain and catalytic domain which contains active site of the enzyme. Concerning the involvement of COX-۲ in inflammation the inhibition of COX-۲ isoform is a pharmacological favorable target for investigators. This study is an attempt to investigate the inhibitory effect of five new imidazole derivatives on COX-۲ enzyme. To better understand the efficiency of binding mode of interesting compounds, docking study was performed via AutodockVina software and the best docking conformations (energetically favorable according to their scoring function were selected for Molecular Dynamic (MD) simulation. The MD simulation was carried out using Gromacs ۲۰۱۸ and the obtained PDB entry ۵ikr, for all compounds of interest. After equilibration of all compounds of interest through NPT ensemble, a production run was executed for ۱۲۰ ns. The MM-PBSA method was applied to estimate binding free energy in the last ۴۰ ns of the MD trajectories. Considering the utilized procedure, it was revealed that the main contribution values in ΔGbinding were van der Waals and electrostatic interactions. Since the ΔGbinding value of two enzyme-inhibitor complexes were less compared with others (-۱۴۷.۶۸۹ kcal/mol for ۵e and -۱۲۹.۲۶۴ kcal/mol for ۵c), selected compounds will be chosen for synthase process. In addition, the average of RMSD value (root mean square deviation) as a standard for stability evaluation of compounds, are as follow: ۵c (۰/۱۸۹۰ Å) and ۵e (۰/۱۸۲۱ Å), which suggest the less deviation relative to the starting structure. As a result, regarding performed analyses, compounds ۵c and ۵e were considered as the more potent inhibitors for COX-۲ enzyme and were chosen for synthase process.

کلیدواژه ها:

Inflammation ، Molecular Docking ، Molecular Dynamic simulation ، MM-PBSA