Searching for pharmacophores in large coordinate data bases and its use in drug design.

Abstract

Pharmacophores, three-dimensional arrangements of chemical groups essential for biological activity, are being proposed in increasing numbers. We have developed a system to search data bases of three-dimensional coordinates for compounds that contain a particular pharmacophore. The coordinates can be derived from experiment (e.g., Cambridge Crystal Database) or be generated from data bases of connection tables (e.g., Cyanamid Laboratories proprietary compounds) via the program CONCORD. We discuss the results of searches for three sample pharmacophores. Two have been proposed by others based on the conformational analysis of active compounds, and one is inferred from the crystal structure of a protein-igand complex. These examples show that such searches can identify classes of compounds that are structurally different from the compounds from which the pharmacophore was derived but are known to have the appropriate biological activity. Occasionally, the searches find bond "frameworks" in which the important groups are rigidly held in the proper geometry. These may suggest new structural classes for synthesis.The function of rational drug design is to relate chemical structure to a specific biological activity and then to use the relationship to select existing compounds for testing or to suggest new compounds for synthesis. Now that threedimensional molecular modeling is widely used, "pharmacophore" models for a variety of biological activities are appearing in the literature in increasing numbers. The concept of a pharmacophore, although based on many simplifying assumptions, is a useful one: a particular spatial arrangement of chemical groups (usually atoms), common to all active molecules, that is recognized by a single receptor. Pharmacophores can be inferred from the structure ofligandreceptor complexes or, when the structure of the receptor is not known, can be deduced by conformational analysis of active compounds, as in the "active analog" approach (1-3). A pharmacophore is usually expressed in three-dimensional terms (distances, angles, volumes), and its atoms may be described by a physical property (cation, hydrogen bond donor, etc.). Often, a pharmacophore will contain one or more "dummy" atoms, which are used to define a geometric entity (centroid of a ring, a lone pair direction, etc.).More than 10 years ago, Gund (4, 5) pointed out how, once a pharmacophore is defined for a particular biological activity, one could gain further insight by finding structures that contain the pharmacophore but are structurally different from the compounds from which the pharmacophore was derived. He described one of the first methods (MOLPAT) to search for pharmacophores in data bases of threedimensional coordinates. At that time, the usefulness of such searches was limited since the three-dimensional data bases available (crystal coordinates or computer-generated conformations of a few compounds) were -mall. Now, however, the data base of crystal coordinates maintained by Cambridge (6) has >60,000 entries. Mo...

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