IDENTIFICATION OF A LEAD MOLECULE FOR INFLAMMATION BY MOLECULAR MECHANICS
Inflammation is the first indication of entry of any foreign molecules that enters in to the immune system, during which COX-2 is being produced in high level. If it persists inflammation will be chronic. To nullify the effect of COX-2, Celecoxib (NSAID/ COX-2 Inhibitor) is given. Having known these facts of NSAID, an attempt was made to enhance the efficiency of NSAID by In-silico method. 3D structure of NSAID is downloaded from NCBI Pubchem Database, and it is treated as ligand molecule. Crystal structure (3D) of cyclooxygenase - 2 is downloaded from PDB database and treated as target receptor for COX-2 inhibitor. The molecular mechanics were calculated using Poisson-Boltzmann model of Open Eye scientific software. A four-stage protocol was set up for energy minimizations of the protein-inhibitor complex. Minimization at each stage was performed using 100 steps of steepest descent and 2000 steps of conjugate gradient algorithms for minimization. The calculated binding free energies of all 10 analogues of COX-2 inhibitors are compared. The calculated binding affinities of the analogue 10 found to a better inhibitor than other lead analogues. It is predicted to be the most potent inhibitor (Ecal (MM) = -13.27) to cyclooxygenase-2 enzyme as compared to all other inhibitor considered in this study. Energy components calculated by performing molecular mechanics calculations, both in explicit solvent and complex states are estimated as Energy= 51.96 (Relative binding free energy). The comparison of the calculated binding free energies for structurally similar inhibitors to cox-2, molecule gave us suitable analogues. These results clearly indicate that before synthesis and testing of new analogue, one can use molecular mechanics based methods for qualitative assessment of relative binding affinities to speed up drug discovery process by eliminating less potent compounds from synthesis.