Optimizing glucokinase activator binding kinetics to lower in vivo hypoglycemia risk

MEDCHEMCOMM(2014)

Cited 10|Views36
No score
Abstract
Activation of glucokinase represents a promising strategy for the treatment of type 2 diabetes; however, drug candidates have failed in clinical trials due to narrow therapeutic index between glucose-lowering efficacy and hypoglycemia. Described herein is a novel strategy for the design of next generation glucokinase activators with increased therapeutic index, which involves the optimization of activator-enzyme binding kinetics (k(on), k(off)). This approach is based on the idea that activator binding kinetics are relevant to pharmacodynamics since the affinity of activator binding to glucokinase is cooperative with glucose such that, the rate at which an activator dissociates may influence the enzyme's sensitivity to changes in physiological glucose concentrations. This study provides a compelling example of using fast-off binding kinetics for developing safe and effective activator drugs targeting glucokinase.
More
Translated text
Key words
Glycogen Metabolism
AI Read Science
Must-Reading Tree
Example
Generate MRT to find the research sequence of this paper
Chat Paper
Summary is being generated by the instructions you defined