Lack of synergy for inhibitors targeting a multi-drug-resistant HIV-1 protease.
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.
King
Nancy M
NM
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
Melnick
Laurence
L
Prabu-Jeyabalan
Moses
M
Nalivaika
Ellen A
EA
Yang
Shiow-Shong
SS
Gao
Yun
Y
Nie
Xiaoyi
X
Zepp
Charles
C
Heefner
Donald L
DL
Schiffer
Celia A
CA
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
D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D019469:Indinavir; D016333:HIV Protease