A systematic study of P 1–P 3 spanning sidechains for the inhibition of HIV-1 protease

• Published in: Bioorganic & medicinal chemistry letters Vol. 5; no. 7; pp. 715 - 720
• Main Authors: Kaldor, Stephen W., Appelt, Krzysztof, Fritz, James E., Hammond, Marlys, Crowell, Thomas A., Baxter, Angela J., Hatch, Steven D., Wiskerchen, MaryAnn, Muesing, Mark A.
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 1995
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/0960-894X(95)00101-X

Using information obtained from the co-crystal structure of an initial peptidomimetic lead complexed with HIV-1 protease, a series of inhibitors was constructed with substituents designed to span from the P 1 to the P 3 pockets of the enzyme. In accord with prediction, systematic extension of the P 1 substituent with large, lipophilic groups leads to enhancements in binding potencies for this class of inhibitors. Surprisingly, inhibitors with large substituents at both P 1 and P 3 are also well-tolerated by the enzyme, providing compounds with subnanomolar binding affinities for HIV-1 protease. Structure-based design has been used to arrive at a new series of potent HIV-1 protease inhibitors incorporating elongated phenylalanine replacements. Crystal structure evidence is provided to support the hypothesis that these new substituents simultaneously occupy the P 1 and P 3 pockets of the enzyme.