title: Lack of synergy for inhibitors targeting a multi-drug-resistant HIV-1 protease.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
authors.forename: Nancy M
authors.initials: NM
authors.lastname: King
authors.forename: Laurence
authors.initials: L
authors.lastname: Melnick
authors.forename: Moses
authors.initials: M
authors.lastname: Prabu-Jeyabalan
authors.forename: Ellen A
authors.initials: EA
authors.lastname: Nalivaika
authors.forename: Shiow-Shong
authors.initials: SS
authors.lastname: Yang
authors.forename: Yun
authors.initials: Y
authors.lastname: Gao
authors.forename: Xiaoyi
authors.initials: X
authors.lastname: Nie
authors.forename: Charles
authors.initials: C
authors.lastname: Zepp
authors.forename: Donald L
authors.initials: DL
authors.lastname: Heefner
authors.forename: Celia A
authors.initials: CA
authors.lastname: Schiffer
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D016503:Drug Delivery Systems; D018432:Drug Resistance, Multiple; D004357:Drug Synergism; D016333:HIV Protease / Q000737:chemistry* / Q000187:drug effects* / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1; D006801:Humans; D019469:Indinavir / Q000494:pharmacology; D009154:Mutation; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D019469:Indinavir; D016333:HIV Protease