Analysis of binding affinities for celecoxib analogues with COX-1 and COX-2 from combined docking and Monte Carlo simulations and insight into the COX-2/COX-1 selectivity
Mlp. Price et Wl. Jorgensen, Analysis of binding affinities for celecoxib analogues with COX-1 and COX-2 from combined docking and Monte Carlo simulations and insight into the COX-2/COX-1 selectivity, J AM CHEM S, 122(39), 2000, pp. 9455-9466
The origins of binding affinity and COX-2/COX-1 selectivity for analogues o
f celecoxib have been explored using an approach that combines docking with
Monte Carlo (MC) simulations. These inhibitors are COX-2-selective nonster
oidal antiinflammatory drugs (NSAIDs) that are of current interest because
the gastrointestinal irritation they cause is reduced compared to that caus
ed by traditional NSAIDs. We report a novel docking method, based on a comb
ined Tabu and Monte Carlo protocol, that determines starting conformations
for MC simulations. Using the docking-predicted starting conformations, rel
ative changes in binding free energies were computed for methyl, ethyl, hyd
roxymethyl, hydroxyl, thiomethyl, methoxy, trifluoromethyl, chloro, fluoro,
and unsubstituted derivatives with the MC free energy perturbation (FEP) m
ethod. The computed free energies are in good accord with IC50 values, and
the structural information from the simulations can be used to explain the
experimentally observed binding trends. In addition, the docking and FEP re
sults have provided clarification of the binding conformation of the phenyl
sulfonamide moiety and the origin of COX-2/COX-1 selectivity. Namely, the C
OX-2 Val --> COX-1 Ile subtitution is accompanied by an unfavorable conform
ational shift of the phenylsulfonamide ring.