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Novel lead structures for p38 MAP kinase via FieldScreen virtual screening.

Abstract：

:p38 MAP kinase has received considerable interest in the pharmaceutical industry and remains a valid and interesting target for the treatment of inflammation. To discover novel p38 inhibitors, we applied the ligand-based virtual screening technique, FieldScreen, to 1.2 million commercially available compounds. Fifty-eight diverse compounds were selected for biological analysis, using molecular field similarity to known inhibitors, while explicitly removing any structure that shared a scaffold with previously reported p38 inhibitors. Of these, 11 (19%) showed >or=20% inhibition of p38 at 10 microM. We chose to prepare analogues of two distinct chemical series resulting in a potential lead compound with pIC(50) of 6.4. Modeling of SAR using FieldAlign, a ligand alignment protocol, was used to rationalize the SAR of the series of thiadiazole based inhibitors.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Cheeseright TJ,Holm M,Lehmann F,Luik S,Göttert M,Melville JL,Laufer S

doi

10.1021/jm801399r

subject

Has Abstract

pub_date

2009-07-23 00:00:00

pages

4200-9

issue

14

eissn

0022-2623

issn

1520-4804

journal_volume

52

pub_type

杂志文章

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