Abstract: 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.