Abstract
Mammalian target of rapamycin (mTOR) is a PI3K-related serine/threonine protein kinase that functions as a master regulator of cellular growth and metabolism, in response to nutrient and hormonal stimuli. mTOR functions in two distinct complexes—mTORC1 is sensitive to rapamycin, while, mTORC2 is insensitive to this drug. Deregulation of mTOR’s enzymatic activity has roles in cancer, obesity, and aging. Rapamycin and its chemical derivatives are the only drugs that inhibit the hyperactivity of mTOR, but numerous side effects have been described due to its therapeutic use. The purpose of this study was to identify new compounds of natural origin that can lead to drugs with fewer side effects. We have used computational techniques (molecular docking and calculated ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) parameters) that have enabled the selection of candidate compounds, derived from marine natural products, SuperNatural II, and ZINC natural products, for inhibitors targeting, both, the ATP and the rapamycin binding sites of mTOR. We have shown experimental evidence of the inhibitory activity of eleven selected compounds against mTOR. We have also discovered the inhibitory activity of a new marine extract against this enzyme. The results have been discussed concerning the necessity to identify new molecules for therapeutic use, especially against aging, and with fewer side effects.
Highlights
The mammalian target of rapamycin is a highly conserved phosphoinositide 3-kinase (PI3K-like) Ser/Thr protein kinase (UniProt P42345), which plays an important role in the center of numerous cellular signaling pathways that control the organization of the cell’s cytoskeleton, autophagy, metabolism, survival and proliferation, and integrates the growth factor-activated and nutrient-sensing pathways [1]
Types protein antibiotic produced by Streptomyces hygroscopicus that forms a complex with the immunophilin FK506 macrolide antibiotic produced by Streptomyces hygroscopicus that forms a complex with the binding protein-12 (FKBP12) (Figure 1), which binds to the FKBP12-rapamycin binding (FRB) domain immunophilin FK506 binding protein-12 (FKBP12) (Figure 1), which binds to the FKBP12-rapamycin of Mammalian target of rapamycin (mTOR) [2] and inhibits its kinase activity [3]
When the results obtained for the rapamycin binding site were analyzed, 4.8% (692 compounds) of the marine natural product database had an average ∆G value less than or equal to −11 kcal/mol
Summary
The mammalian target of rapamycin (mTOR) is a highly conserved phosphoinositide 3-kinase (PI3K-like) Ser/Thr protein kinase (UniProt P42345), which plays an important role in the center of numerous cellular signaling pathways that control the organization of the cell’s cytoskeleton, autophagy, metabolism, survival and proliferation, and integrates the growth factor-activated and nutrient-sensing pathways [1]. MTORC1, which is sensitive to rapamycin and is a macrolide twoMar. types protein antibiotic produced by Streptomyces hygroscopicus that forms a complex with the immunophilin FK506 macrolide antibiotic produced by Streptomyces hygroscopicus that forms a complex with the binding protein-12 (FKBP12) (Figure 1), which binds to the FKBP12-rapamycin binding (FRB) domain immunophilin FK506 binding protein-12 (FKBP12) (Figure 1), which binds to the FKBP12-rapamycin of mTOR [2] and inhibits its kinase activity [3]. MTORC2, in which mTOR forms a protein binding (FRB) domain of mTOR [2] and inhibits its kinase activity [3]. MTORC2, in which complex insensitive to rapamycin [4]. In addition to mTOR, the mTORC1 complex contains the mTOR forms a protein complex insensitive to rapamycin [4]. In addition to mTOR, the mTORC1 following proteins—regulatory-associated protein of mTOR (RAPTOR), proline-rich Akt substrate complex contains the following proteins—regulatory-associated protein of mTOR (RAPTOR), 40 proline-rich kDa (PRAS40), mammalian lethal with Sec protein lethal
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