Molecular modeling and synthesis of inhibitors of herpes simplex virus type 1 uracil-DNA glycosylase

We recently reported the properties of the first selective inhibitors of he rpes simplex virus type 1 (HSV1) uracil-DNA glycosylase (UDG), an enzyme of DNA repair that has been proposed to be required for reactivation of the v irus from latency. 6-(4-Octylanilino)uracil (octAU) was the most potent inh ibitor among a series of 6-(4-alkylanilino)uracils, acting in the micromola r range and without effect against human UDG. A 28.5-kDa catalytic fragment of HSV1 UDG has been crystallized in the presence of uracil, and the struc ture was recently solved. We have used the coordinates of this structure in order to study interaction of our inhibitors with the enzyme, and a model of binding between octAU and UDG has been derived. Starting with the optimi zed model, the activity of several octAU analogues was predicted, and the v alues compared favorably with experimental results found for the synthetic compounds. Several hydrophilic derivatives were predicted and found to be a ctive as UDG inhibitors. These compounds will be useful to determine if UDG , like the viral thymidine kinase, is required for reactivation of HSV1 fro m latency in nerve cells.