The measurement of molecular diversity by receptor site interaction simulation.

The assembly of large compound libraries for the purpose of screening against various receptor targets to identify chemical leads for drug discovery programs has created a need for methods to measure the molecular diversity of such libraries. The method described here, for which we propose the acronym RESIS (for Receptor Site Interaction Simulation), relates directly to this use. A database is built of three-dimensional representations of the compounds in the library and a set of three-point three-dimensional theoretical receptor sites is generated based on putative hydrophobic and polar interactions. A series of flexible, three-dimensional searches is then performed over the database, using each of the theoretical sites as the basis for one such search. The resulting pattern of hits across the grid of theoretical receptor sites provides a measure of the molecular diversity of the compound library. This can be conveniently displayed as a density map which provides a readily comprehensible visual impression of the library diversity characteristics. A library of 7500 drug compounds derived from the CIPSLINEPC databases was characterized with respect to molecular diversity using the RESIS method. Some specific uses for the information obtained from application of the method are discussed. A comparison was made of the results from the RESIS method with those from a recently published two-dimensional approach for assessing molecular diversity using sets of compounds from the Maybridge database (MAY).