DIFFERENT APPROACHES TOWARD AN AUTOMATIC STRUCTURAL ALIGNMENT OF DRUGMOLECULES - APPLICATIONS TO STEROL MIMICS, THROMBIN AND THERMOLYSIN INHIBITORS

A relative comparison of the binding properties of different drug mole cules requires their mutual superposition with respect to various alig nment criteria. In order to validate the results of different alignmen t methods, the crystallographically observed binding geometries of lig ands in the pocket of a common protein receptor have been used. The al ignment function in the program SEAL that calculates the mutual superp osition of molecules has been optimized with respect to these referenc es. Across the reference data set, alignments could be produced that s how mean rms deviations of approximately 1 Angstrom compared to the ex perimental situation. For structures with obvious skeletal similaritie s a multiple-flexible fit, linking common pharmacophoric groups by vir tual springs, has been incorporated into the molecular mechanics progr am MOMO. In order to combine conformational searching with comparative alignments, the optimized SEAL approach has been applied to sets of c onformers generated by MIMUMBA, a program for conformational analysis. Multiple-flexible fits have been calculated for inhibitors of ergoste rol biosynthesis. Sets of different thrombin and thermolysin inhibitor s have been conformationally analyzed and subsequently aligned by a co mbined MIMUMBA/SEAL approach. Since for these examples crystallographi c data on their mutual alignment are available, an objective assessmen t of the computed results could be performed. Among the generated conf ormers, one geometry could be selected for the thrombin and thermolysi n inhibitors that approached reasonably well the experimentally observ ed alignment.