Molecular Docking studies of FKBP12-mTOR inhibitors using binding predictions

Arash Boroumand Nasr; Deepika Ponnala; Someshwar Rao Sagurthi; Ramesh Kumar Kattamuri; Vijaya Kumar Marri; Suresh Gudala; Chandana Lakkaraju; Srinivas Bandaru; Anuraj Nayarisseri

doi:10.6026/97320630011307

Molecular Docking studies of FKBP12-mTOR inhibitors using binding predictions

Bioinformation. 2015 Jun 30;11(6):307-15. doi: 10.6026/97320630011307. eCollection 2015.

Authors

Arash Boroumand Nasr¹, Deepika Ponnala¹, Someshwar Rao Sagurthi², Ramesh Kumar Kattamuri³, Vijaya Kumar Marri³, Suresh Gudala¹, Chandana Lakkaraju¹, Srinivas Bandaru⁴, Anuraj Nayarisseri⁵

Affiliations

¹ Institute of Genetics and Hospital for Genetic Diseases, Osmania University, Hyderabad - 500 016, India.
² Department of Genetics, Osmania University, Hyderabad - 500 007, India.
³ Government General and Chest Hospital, Gandhi Medical College and Osmania Medical College, Hyderabad - 500 038, India.
⁴ 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.
⁵ In silico Research Laboratory, Eminent Biosciences, Indore - 452 010, Madhya Pradesh, India.

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.

Abbreviations: 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.

Keywords: FKBP12; FRB domain; Human oral absorption; Protein-protein interactions; Solubility; mTOR; virtual screening.