Crystallographic Study of a Novel Subnanomolar Inhibitor Provides Insight on the Binding Interactions of Alkenyldiarylmethanes with Human Immunodeficiency Virus-1 Reverse Transcriptase

Two crystal structures have been solved for separate complexes of alkenyldiarylmethane (ADAM) nonnucleoside reverse transcriptase inhibitors (NNRTI) 3 and 4 with HIV-1 reverse transcriptase (RT). The structures reveal inhibitor binding is exclusively hydrophobic in nature and the shape of the inhibi...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2009-10, Vol.52 (20), p.6467-6473
Main Authors: Cullen, Matthew D, Ho, William C, Bauman, Joseph D, Das, Kalyan, Arnold, Eddy, Hartman, Tracy L, Watson, Karen M, Buckheit, Robert W, Pannecouque, Christophe, De Clercq, Erik, Cushman, Mark
Format: Article
Language:English
Subjects:
Animals
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antiviral agents
Biological and medical sciences
Crystallography, X-Ray
HIV Reverse Transcriptase - antagonists & inhibitors
HIV Reverse Transcriptase - chemistry
HIV Reverse Transcriptase - metabolism
HIV-1 - drug effects
HIV-1 - enzymology
Humans
Hydrolysis
Inhibitory Concentration 50
Medical sciences
Methane - blood
Methane - chemistry
Methane - metabolism
Methane - pharmacology
Models, Molecular
Pharmacology. Drug treatments
Protein Binding
Protein Structure, Tertiary
Rats
Reverse Transcriptase Inhibitors - blood
Reverse Transcriptase Inhibitors - chemistry
Reverse Transcriptase Inhibitors - metabolism
Reverse Transcriptase Inhibitors - pharmacology
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Summary:Two crystal structures have been solved for separate complexes of alkenyldiarylmethane (ADAM) nonnucleoside reverse transcriptase inhibitors (NNRTI) 3 and 4 with HIV-1 reverse transcriptase (RT). The structures reveal inhibitor binding is exclusively hydrophobic in nature and the shape of the inhibitor-bound NNRTI binding pocket is unique among other reported inhibitor−RT crystal structures. Primarily, ADAMs 3 and 4 protrude from a large gap in the back side of the binding pocket, placing portions of the inhibitors unusually close to the polymerase active site and allowing 3 to form a weak hydrogen bond with Lys223. The lack of additional stabilizing interactions, beyond the observed hydrophobic surface contacts, between 4 and RT is quite perplexing given the extreme potency of the compound (IC50 ≤ 1 nM). ADAM 4 was designed to be hydrolytically stable in blood plasma, and an investigation of its hydrolysis in rat plasma demonstrated it has a significantly prolonged half-life in comparison to ADAM lead compounds 1 and 2.
ISSN:0022-2623
1520-4804
1520-4804
DOI:10.1021/jm901167t