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

We report here 530 ps molecular dynamics (MD) simulation results on complex es of two non-steroidal antiinflammatory drugs NS398 and indoprofen with cy clooxygenases (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 c onstant, 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 8 Angstrom. The time step for integration was 0.001 ps. The non-bonded pair-list was upgraded after every 20 cycles. Analysis of structure based p arameters was done using sub-averaged coordinates collected at 2 ps interva ls from 330 to 530 ps of MD simulation. Perturbative changes in the enzymes and enzyme-inhibitor complexes were monitored. These are discussed in ligh t of the differential activity of the two drugs. (C) 2000 Elsevier Science B.V. All rights reserved.