A computer assisted receptor mapping approach to the design of anti-AIDS agents directed at HIV reverse transcriptase

The authors take a pharmacophoric approach to the identification of a substrate/inhibitor binding site on HIV-1 RT. A pharmacophore is defined as the spatial arrangement of a set of atoms or groups in a ligand molecule while bound to a given receptor. The pharmacophore´s usefulness is in the assumption that a single one exists for a series of compounds binding at the same receptor site. The superposition of a series of substrate and/or inhibitors along a pharmacophoric pattern provides an enzyme excluded volume, which represents a minimum volume requirement for substrate/inhibitors at the receptor binding site. The structure of HIV-1 RT complexed with dsDNA template-primer has been recently described at 7 Å resolution and is currently being extended to 3 Å. The combination of crystallographic, pharmacophoric, and existing biochemical and genetic data regarding the substrate binding residues will help to generate an accurate structure of the substrate binding domain of HIV-1 RT and aid in the evaluation of new and specific RT inhibitors