Estimation of active conformations of drugs by a new molecular superposing procedure.

We have developed a new program, SUPERPOSE, to superpose two molecules based on the physicochemical properties of functional atoms within individual molecules. SUPERPOSE treats a pseudo-molecule consisting of functional atoms instead of a real molecule. Four types of physicochemical properties--hydrophobicity, presence of a hydrogen-bonding donor, presence of a hydrogen-bonding acceptor and presence of a hydrogen-bonding donor/acceptor--were supposed and a score was given to each overlap. When functional atoms with the same physicochemical properties were overlapped, points were added to the score, and when the functional atoms with different physicochemical properties were overlapped, points were subtracted. We applied SUPERPOSE to 12 pairs of 24 enzyme inhibitors and found that the best scored overlay for each inhibitor pair could successfully reproduce the superposition obtained from X-ray crystallography. Next, we applied SUPERPOSE to estimate the active conformations of the thrombin inhibitors MQPA, 4-TAPAP and NAPAP. Superpositions of conformers sampled by the high-temperature molecular dynamics calculation with respect to the three inhibitors were performed, and 13 sets of conformers having the best common overlay to the three inhibitors were selected. One among 13 sets was consistent with the superposition of the active conformations derived from the X-ray crystallography of the thrombin-inhibitor complexes.