title: Structure-based grafting and identification of kinase-inhibitors to target mTOR signaling pathway as potential therapeutics for glioblastoma.
abstract: Mammalian target of rapamycin (mTOR), a key mediator of PI3K/Akt/mTOR signaling pathway, has recently emerged as a compelling molecular target in glioblastoma. The mTOR is a member of serine/threonine protein kinase family that functions as a central controller of growth, proliferation, metabolism and angiogenesis, but its signaling is dysregulated in various human diseases especially in certain solid tumors including the glioblastoma. Here, considering that there are various kinase inhibitors being approved or under clinical or preclinical development, it is expected that some of them can be re-exploited as new potent agents to target mTOR for glioblastoma therapy. To achieve this, a synthetic pipeline that integrated molecular grafting, consensus scoring, virtual screening, kinase assay and structure analysis was described to systematically profile the binding potency of various small-molecule inhibitors deposited in the protein kinase-inhibitor database against the kinase domain of mTOR. Consequently, a number of structurally diverse compounds were successfully identified to exhibit satisfactory inhibition profile against mTOR with IC50 values at nanomolar level. In particular, few sophisticated kinase-inhibitors as well as a flavonoid myricetin showed high inhibitory activities, which could thus be considered as potential lead compounds to develop new potent, selective mTOR-inhibitors. Structural examination revealed diverse nonbonded interactions such as hydrogen bonds, hydrophobic forces and van der Waals contacts across the complex interface of mTOR with myricetin, conferring both stability and specificity for the mTOR-inhibitor binding.
authors.affiliation: Department of Neurosurgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China. Electronic address: yuhui_cui@126.com.
authors.forename: Yu-Hui
authors.initials: YH
authors.lastname: Cui
authors.affiliation: Department of Neurosurgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
authors.forename: Jiong
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Neurosurgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Xu
authors.affiliation: Department of Neurosurgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
authors.forename: Heng-Li
authors.initials: HL
authors.lastname: Tian
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D016208:Databases, Factual; D055808:Drug Discovery; D005419:Flavonoids / Q000737:chemistry*; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D021281:Quantitative Structure-Activity Relationship; D054852:Small Molecule Libraries / Q000737:chemistry*; D055672:Static Electricity; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D014584:User-Computer Interface
chemical_list: D000970:Antineoplastic Agents; D005419:Flavonoids; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; C040015:myricetin; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: Glioblastoma; Kinase–inhibitor; Rational drug design; mTOR