Identifying pharmacophore containing combinations of scaffold molecules and substituents from a virtual library

摘要

A method for constructing a potentially pharmaceutically useful molecule that displays a predefined pharmacophore associated with a desired biological activity is disclosed. The pharmacophore is first used to screen a virtual library of scaffolds, described by three-dimensional coordinates, in order to identify one or more scaffold(s) which could potentially display substituents that alone or together with scaffold atoms comprise a pharmacophore. The screening process involves first placing rotamers from a virtual library of substituents onto each attachment point of each scaffold, and then examining the resultant Virtual Combinatorial Library (VCL) according to one or more parameters required by the pharmacophore. Preferably, the VCLs are filtered with a series of filters of increasing complexity, in order to eliminate those scaffolds incompatible with the pharmacophore of choice and to identify scaffolds which could display substituents compatible with the pharmacophore, as well the corresponding substituent rotamers themselves. The compatible scaffolds and corresponding substituents are combined to represent one or more molecule or molecules containing the desired pharmacophore. Thus, the method of the present invention is able to efficiently screen very large numbers of molecular entities for the presence of a desired pharmacophore.