Jul 21, 2014

Mechanisms of Action of Autophagy Modulators Dissected by Quantitative Systems Pharmacology Analysis

BioRxiv : the Preprint Server for Biology
Donglei ZhangIvet Bahar

Abstract

Autophagy plays an essential role in cell survival/death and functioning. Modulation of autophagy has been recognized as a promising therapeutic strategy against diseases/disorders associated with uncontrolled growth or accumulation of biomolecular aggregates, organelles or cells including those caused by cancer, aging, neurodegeneration, and liver diseases such as α1-antitrypsin deficiency. Numerous pharmacological agents that enhance or suppress autophagy have been discovered. However, their molecular mechanisms of action are far from clear. Here we collected a set of 225 autophagy modulators and carried out a comprehensive quantitative systems pharmacology (QSP) analysis of their targets using both existing databases and predictions made by our machine learning algorithm. Autophagy modulators include several highly promiscuous drugs (e.g. artenimol and olanzapine acting as activator, fostamatinib as inhibitor, or melatonin as dual-modulator), as well as selected drugs uniquely targeting specific proteins (~30% of modulators). They are mediated by three layers of regulation: (i) pathways involving core autophagy-related (ATG) proteins such as mTOR, AKT, and AMPK; (ii) upstream signaling events that regulates the activity of A...Continue Reading

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Mentioned in this Paper

Calcinus elegans
Biological Markers
Cyartonema elegans
Coleonyx elegans
Cestrum elegans
Clarkia unguiculata
Clathrulina elegans
Cardioglossa elegans
Cymbella elegans
Cyrenella elegans

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