A pseudoreceptor modelling study of the varicella-zoster virus and human thymidine kinase binding sites

Abstract

A representative range of pyrimidine nucleoside analogues that are known 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 interacting ligands, superimposed in such a manner as to define a pharmacophore, the pseudoreceptor modelling technique Yak provides a means of building binding site models of macromolecules for which no three-dimensional experimental structures are available. Once the models have been evaluated by their ability to reproduce experimental binding data [Vedani et al., J. Am. Chem. Soc., 117 (1995) 4987], they can be used for predictive purposes. Calculated and experimental values of relative binding affinity are compared. Our models suggest that the substitution of one residue may be sufficient to determine ligand subtype affinity.

Evolutionary algorithms in computer-aided molecular design

“…One such approach is the construction of a pseudoreceptor, i.e., a hypothetical model, based upon the structures of some known ligands. The Yak program is perhaps the most well-known computational tool for this purpose [132,133]; other methodologies are also emerging [134,135].…”