A MODEL ALLOWING THE DESIGN OF MODIFIED NUCLEOSIDES AS HIV-RT INHIBITORS

A chemical, structural, molecular electrostatic potential (MEP) analys is of modified nucleosides allows the understanding of how nucleosides interact with different receptors. The interaction with kinases is se nsitive to base modifications, while the interaction with the reverse transcriptase receptor HIV active site is more affected by ribose modi fications, The model herein indicates a geometrical lower limit in the width of the modified sugar that corresponds to the 3' erythro positi on. This characteristic allows one to predict a potential activity of the 3' substituted compounds. The 4'-hydroxymethyl group position with respect to the nucleic base is also important for antiviral activity. The model gives the geometric parameters of this position (related to kinetic effects) that corresponds to an increase in the activation en ergy required to fit the active site of the kinases and the RT. Our mo del is compatible with the 3D structure of the HIV RT active site. It allows the design of potent new active compounds where the sugar can b e substituted by any group answering to the defined parameters.