title: 3D-QSAR, molecular dynamics simulations and molecular docking studies of benzoxazepine moiety as mTOR inhibitor for the treatment of lung cancer.
abstract: According to WHO statistics, lung cancer is one of the leading causes of death among all other types of cancer. Many genes get mutated in lung cancer but involvement of EGFR and KRAS are more common. Unavailability of drugs or resistance to the available drugs is the major problem in the treatment of lung cancer. In the present research, mTOR was selected as an alternative target for the treatment of lung cancer which involves PI3K/AKT/mTOR pathway. 28 synthetic mTOR inhibitors were selected from the literature. Ligand based approach (CoMFA and CoMSIA) and structure based approach (molecular dynamics simulations assisted molecular docking study) were applied for the identification of important features of benzoxazepine moiety, responsible for mTOR inhibition. Three different alignments were tried to obtain best QSAR model, of which, distil was found to be the best method, as it gave good statistical results. In CoMFA, Leave One Out (LOO) cross validated coefficients (q(2)), conventional coefficient (r(2)) and predicted correlation coefficient (r(2)pred) values were found to be 0.615, 0.990 and 0.930, respectively. Similarly in CoMSIA, q(2), r(2)ncv and r(2)pred values were found to be 0.748, 0.986 and 0.933, respectively. Molecular dynamics and simulations study revealed that B-chain of mTOR protein was stable at and above 500 FS with respect to temperature (at and above 298 K), Potential energy (at and above 7669.72 kJ/mol) and kinetic energy (at and above 4009.77 kJ/mol). Molecular docking study was performed on simulated protein of mTOR which helped to correlate interactions of amino acids surrounded to the ligand with contour maps generated by QSAR method. Important features of benzoxazepine were identified by contour maps and molecular docking study which would be useful to design novel molecules as mTOR inhibitors for the treatment of lung cancer.
authors.affiliation: Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, S.G. Highway, Chharodi, Ahmedabad 382 481, India.
authors.forename: Udit
authors.initials: U
authors.lastname: Chaube
authors.affiliation: Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, S.G. Highway, Chharodi, Ahmedabad 382 481, India.
authors.forename: Dhara
authors.initials: D
authors.lastname: Chhatbar
authors.affiliation: Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, S.G. Highway, Chharodi, Ahmedabad 382 481, India. Electronic address: hardikbhatt23@hotmail.com.
authors.forename: Hardik
authors.initials: H
authors.lastname: Bhatt
mesh_terms: D000595:Amino Acid Sequence; D001381:Azepines / Q000737:chemistry* / Q000627:therapeutic use; D001665:Binding Sites; D015195:Drug Design; D006801:Humans; D006860:Hydrogen Bonding; D008175:Lung Neoplasms / Q000188:drug therapy*; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D017434:Protein Structure, Tertiary; D021281:Quantitative Structure-Activity Relationship; D016415:Sequence Alignment; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D001381:Azepines; D047428:Protein Kinase Inhibitors; D058570:TOR Serine-Threonine Kinases
keywords: CoMFA; CoMSIA; Lung cancer; Mammalian target of rapamycin (mTOR); Molecular docking; Molecular dynamics simulations