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Bis tertiary amide inhibitors of the HIV-1 protease generated via protein structure-based iterative design.

Abstract：

:A series of potent nonpeptide inhibitors of the HIV protease have been identified. Using the structure of compound 3 bound to the HIV protease, bis tertiary amide inhibitor 9 was designed and prepared. Compound 9 was found to be about 17 times more potent than 3, and the structure of the protein-ligand complex of 9 revealed the inhibitor binds in an inverted binding mode relative to 3. Examination of the protein-ligand complex of 9 suggested several modifications in the P1 and P1' pockets. Through these modifications it was possible to improve the activity of the inhibitors another 100-fold, highlighting the utility of crystallographic feedback in inhibitor design. These compounds were found to have good antiviral activity in cell culture, were selective for the HIV protease, and were orally available in three animal models.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Melnick M,Reich SH,Lewis KK,Mitchell LJ Jr,Nguyen D,Trippe AJ,Dawson H,Davies JF 2nd,Appelt K,Wu BW,Musick L,Gehlhaar DK,Webber S,Shetty B,Kosa M,Kahil D,Andrada D

doi

10.1021/jm960092w

subject

Has Abstract

pub_date

1996-07-05 00:00:00

pages

2795-811

issue

14

eissn

0022-2623

issn

1520-4804

pii

jm960092w

journal_volume

39

pub_type

杂志文章

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