[The development of pharmacophore models for thymidine kinase-dependent virostatic nucleoside analogs]

The most potent drugs in the therapy of Herpes Simplex virus infections belong to the class of guanosine derivatives which bear an acyclic ether substitutent at N-9 (I,II). The initial step in the mode of action was shown to be a monophosphorylation at the primary hydroxyl group of the side chain. The selectivity of the antiviral activity results from the fact that only the virus encoded thymidine kinase is able to bind the acyclic guanosine derivatives. In order to understand this mechanism we try to describe the common pharmacophoric pattern of pyrimidine and purine substrates by molecular modeling methods. It can be shown that a specific binding of guanine could be provided by the enzyme and that flexible side chains are needed instead of deoxyribose to fulfill the requirements of the pharmacophore.