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.AbbreviationsmTOR - 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.

Identification of High-Affinity Small Molecule Targeting IDH2 for the Clinical Treatment of Acute Myeloid Leukemia

“…Subsequently, all cavities were detected to get high volume cavity and hence the highest volume cavity (>2000Å) was selected for docking and to target the active of the IDH2 structure (PDB ID: 5SVN) with the pre-prepared 4 ligands. The docking procedure parameters were selected as required, having a maximum population size of 50, maximum iteration of 1,500 and 0.20Å as grid resolution (Khandelwal et al, 2018;Bandaru, 2017b;Majhi et al, 2018;Nasr et al, 2015). Further, the post-docking process carries hydrogen bonds optimization and energy minimization, Simplex Evolution at max steps 300 and neighbor distance technical setting fast at 1.00 (Sharda S et al, 2019;Ali MA et al, 2019).…”

An In silico Approach to Identify High Affinity Small Molecule Targeting m-TOR Inhibitors for the Clinical Treatment of Breast Cancer

“…Targeted three-dimensional structural coordinates was pre-processed using Protein Preparation Wizard module in Schrödinger Suite (Protein preparation wizard, Schrodinger, 2017) (Sharda et al, 2017;Bandaru et al, 2017) by implying the parameters like assigning bond orders, zero-order bonds to metal atoms, selenomethionine to methionine conversion, filling absent hydrogen's, capping termini, side chains and loops, and removing waters beyond 5 Å distance surrounding the co-crystallized ligand (Bandaru et al, 2017;Shameer et al, 2017;Nasr et al, 2015;Khandekar et al, 2016;Singh et al, 2019). Further, tautomerization and protonation states were predicted in favor of ligand at pH 7.00.…”

Combined 3D-QSAR and Molecular Docking Study on benzo[h][1,6]naphthyridin-2(1H)-one Analogs as mTOR Inhibitors

“…Though the analogues have achieved some clinical success, however, it still has some side effects: mainly in the lower stability, poorer bioavailability and lower water solubility [12] . The latest study found that some small molecule inhibitors of mTOR kinase could inhibit both mTORC 1 and mTORC 2 , such as PP242, a kind of selection mTORC 1 /C 2 inhibitor, can block the Akt kinase by phosphorylating at Ser473 [13][14][15] . Perhaps, the dual inhibitors of mTOR kinase and PI3K are the most effective antitumor inhibitors.…”