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Autophagy and Apoptosis Specific Knowledgebases-guided Systems Pharmacology Drug Research.

ABSTRACT: BACKGROUND:Autophagy and apoptosis are the basic physiological processes in cells that clean up aged and mutant cellular components or even the entire cells. Both autophagy and apoptosis are disrupted in most major diseases such as cancer and neurological disorders. Recently, increasing attention has been paid to understand the crosstalk between autophagy and apoptosis due to their tightly synergetic or opposite functions in several pathological processes. OBJECTIVE:This study aims to assist autophagy and apoptosis-related drug research, clarify the intense and complicated connections between two processes, and provide a guide for novel drug development. METHODS:We established two chemical-genomic databases which are specifically designed for autophagy and apoptosis, including autophagy- and apoptosis-related proteins, pathways and compounds. We then performed network analysis on the apoptosis- and autophagy-related proteins and investigated the full protein-protein interaction (PPI) network of these two closely connected processes for the first time. RESULTS:The overlapping targets we discovered show a more intense connection with each other than other targets in the full network, indicating a better efficacy potential for drug modulation. We also found that Death-associated protein kinase 1 (DAPK1) is a critical point linking autophagy- and apoptosis-related pathways beyond the overlapping part, and this finding may reveal some delicate signaling mechanism of the process. Finally, we demonstrated how to utilize our integrated computational chemogenomics tools on in silico target identification for small molecules capable of modulating autophagy- and apoptosis-related pathways. CONCLUSION:The knowledge-bases for apoptosis and autophagy and the integrated tools will accelerate our work in autophagy and apoptosis-related research and can be useful sources for information searching, target prediction, and new chemical discovery.

SUBMITTER: Fan P

PROVIDER: S-EPMC6774909 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Autophagy and Apoptosis Specific Knowledgebases-guided Systems Pharmacology Drug Research.

Fan Peihao P Wang Nanyi N Wang Lirong L Xie X-Q

Current cancer drug targets 20190101 9

<h4>Background</h4>Autophagy and apoptosis are the basic physiological processes in cells that clean up aged and mutant cellular components or even the entire cells. Both autophagy and apoptosis are disrupted in most major diseases such as cancer and neurological disorders. Recently, increasing attention has been paid to understand the crosstalk between autophagy and apoptosis due to their tightly synergetic or opposite functions in several pathological processes.<h4>Objective</h4>This study aim ...[more]

PMID: 30727895

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Project description:Given the capacity of self-renewal and multilineage differentiation, stem cells are promising sources for use in regenerative medicines as well as in the clinical treatment of certain hematological malignancies and degenerative diseases. Complex networks of cellular signaling pathways largely determine stem cell fate and function. Small molecules that modulate these pathways can provide important biological and pharmacological insights. However, it is still challenging to identify the specific protein targets of these compounds, to explore the changes in stem cell phenotypes induced by compound treatment and to ascertain compound mechanisms of action. To facilitate stem cell related small molecule study and provide a better understanding of the associated signaling pathways, we have constructed a comprehensive domain-specific chemogenomics resource, called StemCellCKB ( http://www.cbligand.org/StemCellCKB/ ). This new cloud-computing platform describes the chemical molecules, genes, proteins, and signaling pathways implicated in stem cell regulation. StemCellCKB is also implemented with web applications designed specifically to aid in the identification of stem cell relevant protein targets, including TargetHunter, a machine-learning algorithm for predicting small molecule targets based on molecular fingerprints, and HTDocking, a high-throughput docking module for target prediction and systems-pharmacology analyses. We have systematically tested StemCellCKB to verify data integrity. Target-prediction accuracy has also been validated against the reported known target/compound associations. This proof-of-concept example demonstrates that StemCellCKB can (1) accurately predict the macromolecular targets of existing stem cell modulators and (2) identify novel small molecules capable of probing stem cell signaling mechanisms, for use in systems-pharmacology studies. StemCellCKB facilitates the exploration and exchange of stem cell chemogenomics data among members of the broader research community.

Dataset Information

Autophagy and Apoptosis Specific Knowledgebases-guided Systems Pharmacology Drug Research.

Publications

Autophagy and Apoptosis Specific Knowledgebases-guided Systems Pharmacology Drug Research.

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