Lack of synergy for inhibitors targeting a multi-drug-resistant HIV-1 protease

UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology

Publication Date


Document Type



Anti-HIV Agents; Binding Sites; Crystallography, X-Ray; Drug Delivery Systems; Drug Resistance, Multiple; Drug Synergism; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Mutation; Protein Conformation; Structure-Activity Relationship; Thermodynamics


Biochemistry, Biophysics, and Structural Biology | Life Sciences | Medicine and Health Sciences | Microbiology


The three-dimensional structures of indinavir and three newly synthesized indinavir analogs in complex with a multi-drug-resistant variant (L63P, V82T, I84V) of HIV-1 protease were determined to approximately 2.2 A resolution. Two of the three analogs have only a single modification of indinavir, and their binding affinities to the variant HIV-1 protease are enhanced over that of indinavir. However, when both modifications were combined into a single compound, the binding affinity to the protease variant was reduced. On close examination, the structural rearrangements in the protease that occur in the tightest binding inhibitor complex are mutually exclusive with the structural rearrangements seen in the second tightest inhibitor complex. This occurs as adaptations in the S1 pocket of one monomer propagate through the dimer and affect the conformation of the S1 loop near P81 of the other monomer. Therefore, structural rearrangements that occur within the protease when it binds to an inhibitor with a single modification must be accounted for in the design of inhibitors with multiple modifications. This consideration is necessary to develop inhibitors that bind sufficiently tightly to drug-resistant variants of HIV-1 protease to potentially become the next generation of therapeutic agents.

DOI of Published Version



Protein Sci. 2002 Feb;11(2):418-29. Link to article on publisher's website

Journal/Book/Conference Title

Protein science : a publication of the Protein Society

Related Resources

Link to Article in PubMed

PubMed ID