AI-Predicted mTOR Inhibitor Reduces Cancer Cell Proliferation and Extends the Lifespan of C. elegans .
Tinka VidovićAlexander DakhovnikOleksii HrabovskyiMichael R MacArthurCollin Yvès EwaldPublished in: International journal of molecular sciences (2023)
The mechanistic target of rapamycin (mTOR) kinase is one of the top drug targets for promoting health and lifespan extension. Besides rapamycin, only a few other mTOR inhibitors have been developed and shown to be capable of slowing aging. We used machine learning to predict novel small molecules targeting mTOR. We selected one small molecule, TKA001, based on in silico predictions of a high on-target probability, low toxicity, favorable physicochemical properties, and preferable ADMET profile. We modeled TKA001 binding in silico by molecular docking and molecular dynamics. TKA001 potently inhibits both TOR complex 1 and 2 signaling in vitro. Furthermore, TKA001 inhibits human cancer cell proliferation in vitro and extends the lifespan of Caenorhabditis elegans , suggesting that TKA001 is able to slow aging in vivo.
Keyphrases
- molecular docking
- cell proliferation
- total knee arthroplasty
- molecular dynamics
- small molecule
- papillary thyroid
- machine learning
- molecular dynamics simulations
- cell cycle
- healthcare
- squamous cell
- pi k akt
- endothelial cells
- public health
- artificial intelligence
- mental health
- density functional theory
- lymph node metastasis
- oxidative stress
- transcription factor
- drug induced
- cancer therapy
- big data
- signaling pathway
- climate change
- induced pluripotent stem cells
- tyrosine kinase
- deep learning