Summary
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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Dammkoehler, R.A., Karasek, S.F., Shands, E.F.B. et al. Constrained search of conformational hyperspace. J Computer-Aided Mol Des 3, 3–21 (1989). https://doi.org/10.1007/BF01590992
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DOI: https://doi.org/10.1007/BF01590992