title: Molecular Docking studies of FKBP12-mTOR inhibitors using binding predictions.
abstract: Mammalian target of rapamycin (mTOR) is a key regulator of cell growth, proliferation and angiogenesis. mTOR signaling is frequently hyper activated in a broad spectrum of human cancers thereby making it a potential drug target. The current drugs available have been successful in inhibiting the mTOR signaling, nevertheless, show low oral bioavailability and suboptimal solubility. Considering the narrow therapeutic window of the available inhibitors, through computational approaches, the present study pursues to identify a compound with optimal oral bioavailability and better solubility properties in addition ensuing high affinity between FKBP12 and FRB domain of mTOR. Current mTOR inhibitors; Everolimus, Temsirolimus Deforolimus and Echinomycin served as parent molecules for similarity search with a threshold of 95%. The query molecules and respective similar molecules were docked at the binding cleft of FKBP12 protein. Aided by MolDock algorithm, high affinity compounds against FKBP12 were retrieved. Patch Dock supervised protein-protein interactions were established between FRB domain of mTOR and ligand (query and similar) bound and free states of FKBP12. All the similar compounds thus retrieved showed better solubility properties and enabled better complex formation of mTOR and FKBP12. In particular Everolimus similar compound PubChem ID: 57284959 showed appreciable drugs like properties bestowed with better solubility higher oral bioavailability. In addition this compound brought about enhanced interaction between FKBP12 and FRB domain of mTOR. In the study, we report Everolimus similar compound PubChem ID: 57284959 to be potential inhibitor for mTOR pathway which can overcome the affinity and solubility concerns of current mTOR drugs.
  
  
  BACKGROUND
  mTOR - Mammalian Target of Rapamycin, FRB domain - FKBP12-rapamycin associated protein, FKBP12 - FK506-binding protein 12, OPLS - Optimized Potentials for Liquid Simulations, Akt - RAC-alpha serine/threonine-protein kinase, PI3K - phosphatidylinositide 3-kinases.
authors.affiliation: Institute of Genetics and Hospital for Genetic Diseases, Osmania University, Hyderabad - 500 016, India.
authors.forename: Arash Boroumand
authors.initials: AB
authors.lastname: Nasr
authors.affiliation: Institute of Genetics and Hospital for Genetic Diseases, Osmania University, Hyderabad - 500 016, India.
authors.forename: Deepika
authors.initials: D
authors.lastname: Ponnala
authors.affiliation: Department of Genetics, Osmania University, Hyderabad - 500 007, India.
authors.forename: Someshwar Rao
authors.initials: SR
authors.lastname: Sagurthi
authors.affiliation: Government General and Chest Hospital, Gandhi Medical College and Osmania Medical College, Hyderabad - 500 038, India.
authors.forename: Ramesh Kumar
authors.initials: RK
authors.lastname: Kattamuri
authors.affiliation: Government General and Chest Hospital, Gandhi Medical College and Osmania Medical College, Hyderabad - 500 038, India.
authors.forename: Vijaya Kumar
authors.initials: VK
authors.lastname: Marri
authors.affiliation: Institute of Genetics and Hospital for Genetic Diseases, Osmania University, Hyderabad - 500 016, India.
authors.forename: Suresh
authors.initials: S
authors.lastname: Gudala
authors.affiliation: Institute of Genetics and Hospital for Genetic Diseases, Osmania University, Hyderabad - 500 016, India.
authors.forename: Chandana
authors.initials: C
authors.lastname: Lakkaraju
authors.affiliation: Institute of Genetics and Hospital for Genetic Diseases, Osmania University, Hyderabad - 500 016, India ; National Institute of Pharmaceutical Education and Research, Hyderabad - 500 037, India.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Bandaru
authors.affiliation: In silico Research Laboratory, Eminent Biosciences, Indore - 452 010, Madhya Pradesh, India.
authors.forename: Anuraj
authors.initials: A
authors.lastname: Nayarisseri
keywords: FKBP12; FRB domain; Human oral absorption; Protein-protein interactions; Solubility; mTOR; virtual screening