Methodological developments toward computational drug design with applications to COX-2-selective ligands.

摘要

Non-bonded and torsional parameters for carboxylate esters, nitriles, nitroalkanes, and alkenes have been developed for the OPLS-AA force field. These parameters were fit to reproduce ab initio gas-phase structures, experimental condensed-phase structural and thermodynamic properties, and experimental free energies of hydration. The computed densities, heats of vaporization, and heat capacities are in excellent agreement with experimental values. These new parameters permit accurate calculations on compounds containing a wider variety of functional groups, some of which are present in common drugs.; The origins of binding affinity and COX-2/COX-1 selectivity for analogs of celecoxib have been explored using an approach that combines docking with Monte Carlo (MC) simulations. These inhibitors are COX-2-selective non-steroidal anti-inflammatory drugs (NSAID) that are of current interest for their reduced gastrointestinal irritation compared to traditional NSAIDs. A novel docking method is reported, based on a combined Tabu and Monte Carlo protocol, that determines starting conformations for MC simulations. Using the docking-predicted starting conformations, relative changes in binding free energies were computed for methyl, ethyl, hydroxymethyl, hydroxyl, thiomethyl, methoxy, trifluoromethyl, chloro, fluoro, and unsubstituted derivatives with the MC Free Energy Perturbation (FEP) method. 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 results have provided clarification of the binding conformation of the phenylsulfonamide moiety and the origin of COX-2/COX-1 selectivity. Namely, the COX-2 Val → COX-1 Ile subtitution is accompanied by an unfavorable conformational shift of the phenylsulfonamide ring as well as a steric clash between the methyl group of Ile and one sulfonamide oxygen of the ligand.