530 ps molecular dynamics simulation of indoprofen and NS398 with COX-1 and COX-2. Study of perturbative changes in the complexes

Abstract

We report here 530ps molecular dynamics (MD) simulation results on complexes of two non-steroidal antiinflammatory drugs NS398 and indoprofen with cyclooxygenases (COX-1 and COX-2). Both the drugs were docked manually in the catalytic cavity of the enzymes on the basis of structural information on COX-1 and COX-2 with different inhibitors using energy grid based in-house docking program IMF-1. The MD simulations were carried out in vacuum, using force field parameters from PARM96.DAT and distance dependent dielectric constant, with scaling factor for 1–4 electrostatic interaction equal to 2.0. Both energy minimization and MD simulations were carried out using Sander's module of AMBER 5.0 with cut-off distance for non-bonded pair list equal to 8Å. The time step for integration was 0.001ps. The non-bonded pair-list was upgraded after every 20 cycles. Analysis of structure based parameters was done using sub-averaged coordinates collected at 2ps intervals from 330 to 530ps of MD simulation. Perturbative changes in the enzymes and enzyme–inhibitor complexes were monitored. These are discussed in light of the differential activity of the two drugs.