ABSTRACT
We were able to alter this relatively simple pyrone with a series of modifications, principally in the P2 and P2-prime sites, which very rapidly led to nanomolar level inhibitors and represented legitimate advances in non-peptide based HIV protease inhibitors. This has now been extended to an interesting mol-ecule whose IC50 is 5 nm. It has a different structure, but nonetheless binds in the active site, does not use water within the binding site, and is quite different from the first-and second-generation inhibitors [7]. This demonstrates the power of structure-based drug design, coming originally from a screening approach, to yield a drug candidate lead.
