当前位置： SCI文献检索 > JOURNAL OF MEDICINAL CHEMISTRY期刊下所有文献 > Definitive Metabolite Identification Coupled with Automated Ligand Identification System (ALIS) Technology: A Novel Approach to Uncover Structure-Activity Relationships and Guide Drug Design in a Factor IXa Inhibitor Program.

Definitive Metabolite Identification Coupled with Automated Ligand Identification System (ALIS) Technology: A Novel Approach to Uncover Structure-Activity Relationships and Guide Drug Design in a Factor IXa Inhibitor Program.

Abstract：

:A potent and selective Factor IXa (FIXa) inhibitor was subjected to a series of liver microsomal incubations, which generated a number of metabolites. Using automated ligand identification system-affinity selection (ALIS-AS) methodology, metabolites in the incubation mixture were prioritized by their binding affinities to the FIXa protein. Microgram quantities of the metabolites of interest were then isolated through microisolation analytical capabilities, and structurally characterized using MicroCryoProbe heteronuclear 2D NMR techniques. The isolated metabolites recovered from the NMR experiments were then submitted directly to an in vitro FIXa enzymatic assay. The order of the metabolites' binding affinity to the Factor IXa protein from the ALIS assay was completely consistent with the enzymatic assay results. This work showcases an innovative and efficient approach to uncover structure-activity relationships (SARs) and guide drug design via microisolation-structural characterization and ALIS capabilities.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Zhang T,Liu Y,Yang X,Martin GE,Yao H,Shang J,Bugianesi RM,Ellsworth KP,Sonatore LM,Nizner P,Sherer EC,Hill SE,Knemeyer IW,Geissler WM,Dandliker PJ,Helmy R,Wood HB

doi

10.1021/acs.jmedchem.5b01293

subject

Has Abstract

pub_date

2016-03-10 00:00:00

pages

1818-29

issue

5

eissn

0022-2623

issn

1520-4804

journal_volume

59

pub_type

杂志文章

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