title: New potential inhibitors of mTOR: a computational investigation integrating molecular docking, virtual screening and molecular dynamics simulation.
abstract: 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.
authors.affiliation: a Health Sciences Postgraduate Program of Federal University of Health Sciences of Porto Alegre - UFCSPA , Porto Alegre City , Brazil.
authors.forename: Roger
authors.initials: R
authors.lastname: Kist
authors.affiliation: a Health Sciences Postgraduate Program of Federal University of Health Sciences of Porto Alegre - UFCSPA , Porto Alegre City , Brazil.|b Pharmacosciences Department of Federal University of Health Sciences of Porto Alegre - UFCSPA , Porto Alegre City , Brazil.
authors.forename: Rafael Andrade
authors.initials: RA
authors.lastname: Caceres
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry*; D000495:Allosteric Site; D000903:Antibiotics, Antineoplastic / Q000737:chemistry*; D015195:Drug Design; D006801:Humans; D007700:Kinetics; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D000072757:Protein Conformation, beta-Strand; D054730:Protein Interaction Domains and Motifs; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D020123:Sirolimus / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D013816:Thermodynamics; D014584:User-Computer Interface
chemical_list: D000903:Antibiotics, Antineoplastic; D008024:Ligands; D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: mTOR; molecular docking simulation; molecular dynamics; no ATP-competitive inhibitors; virtual screening