Ligand-based 3-D pharmacophore generation and molecular docking of mTOR kinase inhibitors

Abstract

The 3-D structure of the human mTOR kinase domain was modeled based on the crystal structure of PI3Kγ using comparative modeling methods, and the ATP-binding site of mTOR was characterized. The mTOR kinase 3-D model structure is similar to the structure of the PI3Kγ kinase domain, and exhibits great similarity to PI3Kγ at the active site of the kinase. Pharmacophore generation, the docking of mTOR inhibitors, and molecular dynamics (MD) simulations of mTOR–inhibitor docked complexes were carried out in this work. The best pharmacophore model generated from 27 ATP-competitive mTOR inhibitors comprised two hydrogen-bond acceptors, one aromatic ring, and one hydrophobic feature. These 27 inhibitors were docked into the ATP-binding site comprising the DFG motif, and the interactions in each protein–inhibitor complex were characterized. Mapping the pharmacophore model onto the docked inhibitors explained the specificity of the features of the pharmacophore and how they were arranged inside the active site of mTOR kinase. MD studies revealed important structural features, such as the large hydrophobic pocket “HP” and hydrophilic pocket “A1,” and the solvent-exposed hydrophilic pocket “A2” at the active site of mTOR. Our results provide structural models of mTOR–inhibitor complexes and clues that should aid in the design of better mTOR kinase inhibitors.