Importance of molecular flexibility for the resistance of HIV-1 protease inhibitors

BACKGROUND: A major obstacle to antiviral therapy for HIV is the emergence of drug resistance. JE-2147 (KNI-764) is a novel inhibitor of HIV-1 protease that has potent antiviral activity and a favorable pharmacokinetic profile. The structure of the enzyme-inhibitor complex should lead to a better understanding of the structural basis for its tight binding properties and to its resistance profiles. METHODS: The three-dimensional crystal structures of JE-2147 and an analog bound to both wild type and 184V mutant HIV protease were determined to 2.1-1.9 A resolution with R-factors of 18.6-19.0%. RESULTS: JE-2147 is structurally related to KNI-272 but contains a methylbenzyl group in the P2' position that makes novel interactions with the wild type enzyme. Two water molecules make bridging hydrogen bonds between the inhibitor and the enzyme. The conformation of the P2' o-methylbenzyl substituent of JE-2147 in the complex with the 184V mutant differed from that of wild type. In addition, rearrangements of the ST side chains from the mutant and wild type enzymes were observed. An analog of JE-2147 that contains a P2' t-butyl substituent shows increased levels of resistance to the 184V mutant protease, but did not exhibit the structural rearrangements seen with JE-2147, in complexes with the mutant enzyme, presumably because of the rigidity of the bulky t-butyl group. CONCLUSIONS: The comparison of the crystal structures of JE-2147 and an analog bound to wild type and 184V mutant HIV proteases indicate that molecular flexibility is an important aspect in the design of inhibitors which are effective at binding to both wild type and mutant HIV protease.

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