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

International Journal of Molecular Sciences

Ivet Bahar¹  Fen Pei¹  Bing Liu¹  Qingya Shi¹  Gary A. Silverman²  David H. Perlmutter²  Stephen C. Pak² 

[1] Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, PA 15213, USA;Department of Pediatrics, School of Medicine, Washington University in St. Louis, MO 63130, USA;

关键词: autophagy;    quantitative systems pharmacology;    signal transduction;    machine learning;    drug-target interactions;    mechanism of action;   

DOI  :  10.3390/ijms21082855

来源: DOAJ

【 摘 要 】

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 1-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 activators, fostamatinib as an inhibitor, or melatonin as a dual-modulator) as well as selected drugs that uniquely target 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 regulate the activity of ATG pathways such as calcium-, cAMP-, and MAPK-signaling pathways; and (iii) transcription factors regulating the expression of ATG proteins such as TFEB, TFE3, HIF-1, FoxO, and NF-κB. Our results suggest that PKA serves as a linker, bridging various signal transduction events and autophagy. These new insights contribute to a better assessment of the mechanism of action of autophagy modulators as well as their side effects, development of novel polypharmacological strategies, and identification of drug repurposing opportunities.

【 授权许可】

Unknown