Nonpeptidic potent HIV-1 protease inhibitors

From an initial mass screening lead, (IC50: 3 microM) and information derived from the X-ray crystallographic structure of a related analog, complexed with HIV protease (PR), the design of more potent inhibitors has been advanced. Various structure-guided approaches to fill P1' and P2' pockets using this pyran-2-one template, molecular modeling and X-ray crystallographic studies led to potent compounds. Of particular significance to the design of this series of inhibitors is the displacement of key structural waters. The binding modes of a series of pyran-2-one analogs and comparison of binding modes with different pyran-2-ones, are highlighted. Noteworthy was the discovery of a highly potent (IC50: 0.007 microM) pyran-2-one derivative, containing novel P1' and P2' functionalization and possessing no chiral centers and having low molecular weight. Pyran-2-ones possessing appended groups to reach to the S3 pocket of the enzyme via tethering on the 6-phenyl ring of pyran-2-one ring is also discussed.