Investigation of Macrocyclic mTOR Modulators of Rapamycin Binding Site via Pharmacoinformatics Approaches

Abstract

The PI3K/Akt/mTOR is an essential intracellular signaling pathway in which the serine/threonine mTOR kinase portrays a major role in cell growth, proliferation and survival. The mTOR kinase is frequently dysregulated in a broad spectrum of cancers, thus making it a potential target. Rapamycin and its analogs (rapalogs) allosterically inhibit mTOR, thereby dodging the deleterious effects prompted by ATP-competitive mTOR inhibitors. However, the available mTOR allosteric site inhibitors exhibit low oral bioavailability and suboptimal solubility. Bearing in mind this narrow therapeutic window of the current allosteric mTOR inhibitors, an in silico study was designed in search of new macrocyclic inhibitors. The macrocycles from the ChemBridge database (12,677 molecules) were filtered for their drug-likeness properties and the procured compounds were subjected for molecular docking within the binding cleft between FKBP25 and FRB domains of mTOR. The docking analysis resulted with 15 macrocycles displaying higher scores than the selective mTOR allosteric site inhibitor, DL001. The docked complexes were refined by subsequent molecular dynamics simulations for a period of 100 ns. Successive binding free energy computation revealed a total of 7 macrocyclic compounds (HITS) demonstrating better binding affinity than DL001, towards mTOR. The consequent assessment of pharmacokinetic properties resulted in HITS with similar or better properties than the selective inhibitor, DL001. The HITS from this investigation could act as effective mTOR allosteric site inhibitors and serve as macrocyclic scaffolds for developing compounds targeting the dysregulated mTOR.

Keywords: Binding free energy; MM/PBSA; Molecular Dynamics Simulations; Molecular docking; Per-residue energy contribution; Virtual screening; mTOR.