Estimation of active conformations of drugs by a new molecular superposingprocedure

We have developed a new program, SUPERPOSE, to superpose two molecules base d on the physicochemical properties of functional atoms within individual m olecules. SUPERPOSE treats a pseudo-molecule consisting of functional atoms instead of a real molecule. Four types of physicochemical properties - hyd rophobicity, presence of a hydrogen-bonding donor, presence of a hydrogen-b onding acceptor and presence of a hydrogen-bonding donor/acceptor - were su pposed and a score was given to each overlap. When functional atoms with th e same physicochemical properties were overlapped, points were added to the score, and when the functional atoms with different physicochemical proper ties were overlapped, points were subtracted. We applied SUPERPOSE to 12 pa irs of 24 enzyme inhibitors and found that the best scored overlay for each inhibitor pair could successfully reproduce the superposition obtained fro m X-ray crystallography. Next, we applied SUPERPOSE to estimate the active conformations of the thrombin inhibitors MQPA, 4-TAPAP and NAPAP. Superposi tions of conformers sampled by the high-temperature molecular dynamics calc ulation with respect to the three inhibitors were performed, and 13 sets of conformers having the best common overlay to the three inhibitors were sel ected. One among 13 sets was consistent with the superposition of the activ e conformations derived from the X-ray crystallography of the thrombin-inhi bitor complexes.