Structure-based design of inhibitors of HIV-1 reverse transcriptase: A potential class of bidentate nonnucleoside inhibitors

A design for nonnucleoside compounds with high specificity towards HIV-1 reverse transcriptase (RT) has been developed by means of a structure-based drug design approach. Crystal structures of HIV-1 RT complexed with different nonnucleoside inhibitors served as the basis for this design. An important feature of the model inhibitors is that they not only retain the structural and electronic specificity of the nonnucleosides to bind to the structurally conserved region of RT but also have the ability to interact, by virtue of their additional structural motif, with one of the catalytically important and conserved aspartate residues at the polymerase active site of the enzyme. Computations of the energy of interactions and the free energy of solvation have suggested that this bidentate class of nonnucleoside inhibitors will have significantly higher binding affinity than their parent nonnucleoside inhibitor compounds.