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Article

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

1
Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
2
School of Medicine, Tsinghua University, Beijing 100084, China
3
Department of Pediatrics, School of Medicine, Washington University in St. Louis, St. Louis, MO 63130, USA
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(8), 2855; https://doi.org/10.3390/ijms21082855
Received: 25 March 2020 / Revised: 14 April 2020 / Accepted: 16 April 2020 / Published: 19 April 2020
(This article belongs to the Special Issue Autophagy in Health, Ageing and Disease 2.0)
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 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. View Full-Text
Keywords: autophagy; quantitative systems pharmacology; signal transduction; machine learning; drug-target interactions; mechanism of action; mTOR; PKA; PI3K autophagy; quantitative systems pharmacology; signal transduction; machine learning; drug-target interactions; mechanism of action; mTOR; PKA; PI3K
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MDPI and ACS Style

Shi, Q.; Pei, F.; Silverman, G.A.; Pak, S.C.; Perlmutter, D.H.; Liu, B.; Bahar, I. Mechanisms of Action of Autophagy Modulators Dissected by Quantitative Systems Pharmacology Analysis. Int. J. Mol. Sci. 2020, 21, 2855. https://doi.org/10.3390/ijms21082855

AMA Style

Shi Q, Pei F, Silverman GA, Pak SC, Perlmutter DH, Liu B, Bahar I. Mechanisms of Action of Autophagy Modulators Dissected by Quantitative Systems Pharmacology Analysis. International Journal of Molecular Sciences. 2020; 21(8):2855. https://doi.org/10.3390/ijms21082855

Chicago/Turabian Style

Shi, Qingya, Fen Pei, Gary A. Silverman, Stephen C. Pak, David H. Perlmutter, Bing Liu, and Ivet Bahar. 2020. "Mechanisms of Action of Autophagy Modulators Dissected by Quantitative Systems Pharmacology Analysis" International Journal of Molecular Sciences 21, no. 8: 2855. https://doi.org/10.3390/ijms21082855

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