A PSEUDORECEPTOR MODELING STUDY OF THE VARICELLA-ZOSTER VIRUS AND HUMAN THYMIDINE KINASE BINDING-SITES

A representative range of pyrimidine nucleoside analogues that are kno wn to inhibit herpes simplex virus (HSV) replication have been used to construct receptor binding site models for the varicella-zoster virus (VZV), thymidine kinase (TK) and human TK1. Given a set of interactin g ligands, superimposed in such a manner as to define a pharmacophore, the pseudoreceptor modelling technique Yak provides a means of buildi ng binding site models of macromolecules for which no three-dimensiona l experimental structures are available. Once the models have been eva luated by their ability to reproduce experimental binding data [Vedani et al., J. Am. Chem. Sec., 117 (1995) 4987], they can be used for pre dictive purposes. Calculated and experimental values of relative bindi ng affinity are compared. Our models suggest that the substitution of one residue may be sufficient to determine ligand subtype affinity.