A systematic study of P1–P3 spanning sidechains for the inhibition of HIV-1 protease
1995
Abstract 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.
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