Journal
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
Volume 35, Issue 16, Pages 3555-3568Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/07391102.2016.1262279
Keywords
mTOR; no ATP-competitive inhibitors; molecular docking simulation; virtual screening; molecular dynamics
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Funding
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico [478603/2012-6]
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The mTOR (mammalian or mechanistic Target Of Rapamycin), a complex metabolic pathway that involves multiple steps and regulators, is a major human metabolic pathway responsible for cell growth control in response to multiple factors and that is dysregulated in various types of cancer. The classical inhibition of the mTOR pathway is performed by rapamycin and its analogs (rapalogs). Considering that rapamycin binds to an allosteric site and performs a crucial role in the inhibition of the mTOR complex without causing the deleterious side effects common to ATP-competitive inhibitors, we employ ligand-based drug design strategies, such as virtual screening methodology, computational determination of ADME/Tox properties of selected molecules, and molecular dynamics in order to select molecules with the potential to become non-ATP-competitive inhibitors of the mTOR enzymatic complex. Our findings suggest five novel potential mTOR inhibitors, with similar or better properties than the classic inhibitor complex, rapamycin.
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