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The rational design of a novel potent analogue of the 5'-AMP-activated protein kinase inhibitor compound C with improved selectivity and cellular activity.

ABSTRACT: We have designed and synthesized analogues of compound C, a non-specific inhibitor of 5'-AMP-activated protein kinase (AMPK), using a computational fragment-based drug design (FBDD) approach. Synthesizing only twenty-seven analogues yielded a compound that was equipotent to compound C in the inhibition of the human AMPK (hAMPK) ?2 subunit in the heterotrimeric complex in vitro, exhibited significantly improved selectivity against a subset of relevant kinases, and demonstrated enhanced cellular inhibition of AMPK.

SUBMITTER: Machrouhi F

PROVIDER: S-EPMC2957560 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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The rational design of a novel potent analogue of the 5'-AMP-activated protein kinase inhibitor compound C with improved selectivity and cellular activity.

Machrouhi Fouzia F Ouhamou Nouara N Laderoute Keith K Calaoagan Joy J Bukhtiyarova Marina M Ehrlich Paula J PJ Klon Anthony E AE

Bioorganic & medicinal chemistry letters 20100919 22

We have designed and synthesized analogues of compound C, a non-specific inhibitor of 5'-AMP-activated protein kinase (AMPK), using a computational fragment-based drug design (FBDD) approach. Synthesizing only twenty-seven analogues yielded a compound that was equipotent to compound C in the inhibition of the human AMPK (hAMPK) α2 subunit in the heterotrimeric complex in vitro, exhibited significantly improved selectivity against a subset of relevant kinases, and demonstrated enhanced cellular i ...[more]

PMID: 20932747

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Project description:Chromatographic characterization and parameterization studies targeting many solutes require the judicious choice of operating conditions to minimize analysis time without compromising the accuracy of the results. To minimize analysis time, solutes are often grouped into a small number of mixtures; however, this increases the risk of peak overlap. While multivariate curve resolution methods are often able to resolve analyte signals based on their spectral qualities, these methods require that the chromatographically overlapped compounds have dissimilar spectra. In this work, a strategy for grouping compounds into sample mixtures containing solutes with distinct spectral and, optionally, with distinct chromatographic properties, in order to ensure successful solute resolution either chromatographically or with curve resolution methods is proposed. We name this strategy rational design of mixtures (RDM). RDM utilizes multivariate selectivity as a metric for making decisions regarding group membership (i.e., whether to add a particular solute to a particular sample). A group of 97 solutes was used to demonstrate this strategy. Utilizing both estimated chromatographic properties and measured spectra to group these 97 analytes, only 12 groups were required to avoid a situation where two or more solutes in the same group could not be resolved either chromatographically (i.e., they have significantly different retention times) or spectrally (i.e., spectra are different enough to enable resolution by curve resolution methods). When only spectral properties were utilized (i.e., the chromatographic properties are unknown ahead of time) the number of groups required to avoid unresolvable overlaps increased to 20. The grouping strategy developed here will improve the time and instrument efficiency of studies that aim to obtain retention data for solutes as a function of operating conditions, whether for method development or determination of the chromatographic parameters of solutes of interest (e.g., k w ).

Dataset Information

The rational design of a novel potent analogue of the 5'-AMP-activated protein kinase inhibitor compound C with improved selectivity and cellular activity.

Publications

The rational design of a novel potent analogue of the 5'-AMP-activated protein kinase inhibitor compound C with improved selectivity and cellular activity.

Similar Datasets

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