Computer simulation of the interaction of non-steroidal anti-inflammatory drugs: Indoprofen and NS398 with cyclooxygenase

We have applied computer simulation technique to study interaction of two a nti-inflammatory drugs (NSAIDs) indoprofen and NS398 with cyclooxygenase (C OX-1 and COX-2) enzymes. We have also investigated conformational flexibili ty of the two drugs by systematic search and simulated annealing molecular dynamics (SAMD) methods. Both the drugs were docked in the cyclooxygenase c hannel using in house docking program IMF1. The complexes were energy minim ised by molecular mechanics (MM) method. These were heated for 30 picosecon ds (ps), equilibrated for 110 ps at 300K and subjected to 'production simul ation' for 110 ps by molecular dynamics (MD) method using Sanderis module o f AMBER 5.0 package and united atom force field mostly from PARM96.DAT. Int egration was carried out with time step of 0.001 ps, distance dependent di- electric constant with scaling factor 2.0 for 1-4 interaction and cut-off d istance for non-bonded pair-list equal to 8 Angstrom. The non-bonded pair-l ist was upgraded after every 20 cycles. The coordinate output from MD traje ctories is analysed using analysis package of AMBER 5.0, MOLMOL, P-CURVES 3 .0 and in house packages: ANALMD, ANALP1. We have observed perturbative cha nges in COX-1 and COX-2 structures due to indoprofen and NS398. In case of indoprofen specific changes between COX-1 and COX-2 were noted in helix D, H6, S6 and helix H8 in the cyclooxygenase cavity. In case of NS398 these we re in helix B in membrane binding domain, helix H6, S8 and S10 in cyclooxyg enase cavity and helices H14-H16 in small lobe close to haem binding region . Implications of these results in enzyme selectivity by NSAIDs is discusse d here.