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We introduce a new method for determining pharmacophore or active site geometries by analysis of the structures of a series of active compounds. The method, constrained search, and the key concepts on which it is based, is described and illustrated by its application to 28 potent inhibitors of angiotensin-converting enzyme (ACE). The data set is one utilized by Mayer et al. [J. Comput.-Aided Mol. Design, 1 (1987) 3-16] to determine a unique geometry for the active site. Our experiment validated the previously reported results, obtained by a systematic search, while reducing the computer time requirement by more than two orders of magnitude. The experiment also identified a previously unrecognized alternative active site geometry for the ACE series.

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Three new strategies for sampling the conformation space accessible to a series of structurally diverse, flexible molecules are defined and compared to samples obtained using a fixed-grid torsion angle sampling strategy. A set of 28 potent inhibitors of angiotensin converting enzyme selected by Mayer et al. [J. Comput.-Aided Mol. Design, 1 (1987) 3] and the unrestricted active-site model proposed by Waller et al. [to be published] are used to produce a realistic experimental setting. We modified our Constrained Search algorithm [Dammkoehler et al., J. Comput.-Aided Mol. Design, 3 (1989) 3] to support these new sampling strategies, performing a series of 64 simulations (search experiments) and generating a large set of sterically allowed conformations. In each experiment, we systematically vary the internal torsion angles in each molecule using one of the sampling strategies. The common orientations of preselected functional groups thought to represent those dominating the interaction with the enzyme and presented by the set of molecules are classified and recorded for each experiment. Pairwise distances between groups are used to characterize the geometry of the common orientations. The results of each experiment, represented by a set of distance values, are compared and combined to evaluate the completeness of the conformational sampling. While no pure strategy or single search experiment was found to be adequate to fully explore the set of common sterically allowed conformations, a new sampling technique, called adaptive radial sampling, is shown to be significantly more complete than the commonly used fixed grid sampling.

A conceptually and computationally integrated approach to pharmacophore model validation is discussed at length. It allows one, for the first time, to address the question of pharmacophore existence and assessment of its uniqueness in a rigorous and quantitative manner. The approach has been effectively applied to the analysis of seventeen structurally diverse potent inhibitors of angiotensin converting enzyme and the resultant pharmacophore greatly refines the previously suggested models.

A molecular mechanics program (Maximin) is described with emphasis on its distinctive features. With Maximin, energy can be minimized while maintaining specified geometric relationships within and/or among given sets of atoms. Additionally, two alternative methods for conformational comparisons are supported: a set of flexible molecules can be mapped onto a rigid reference structure, or treating all molecules as flexible entities, one can minimize the conformational variance of the set. The latter method is described here for the first time. Calculations of methotrexate‐dihydrofolate reductase interaction energy, and the analysis of a series of structurally diverse inhibitors of angiotensin converting enzyme are reported. Algorithmic description of the original features of Maximin is also provided.

The paper presents and illustrates a method which uses numerical integration of the van der Waals envelope(s) to calculate with desired accuracy the molecular van der Waals volume and the three-dimensional molecular shape descriptor defined as the twin-number [OV(α, β); NOV(β, α), where OV and NOV represent the overlapping and, respectively, the nonoverlapping van der Waals volumes of the molecules α and ß superimposed according to appropriate criteria.