Molecular Docking and Pharmacokinetic of Highly Specific Novel Pan-Mtor Inhibitors against Solid Tumors

Abstract

Mechanistic/mammalian target of rapamycin (mTOR) a serine/threonine kinase belonging to PI3K/Akt/mTOR pathway is involved in different cellular functions cell survival, metabolism, growth, proliferation, apoptosis and autophagy. PanmTOR inhibitors are targeted towards mTOR dysregulation, inhibiting the kinase domain of both mTORC1 and mTORC2. The present study analyzes the binding modes and molecular interactions of highly specific mTOR inhibitors, AZD8055 and its sister compoundAZD2014using computational approach. Both inhibitors proved to be effective against solid tumors in vitro and in vivo. Docking analysis was performed using Auto Dock Vina, conformations were scored based upon their binding energy (kcal/mol) and illustrated using Discovery Studio Visualizer 4.5 version. Inhibitors fit between N-and C-lobes of mTOR kinase domain into the inner hydrophobic core. The results indicated interactions with distinctive mTOR residues Trp-2239, Leu-2185 and newly developed interactions with Asp-2375 for AZD2014 and with Ala-2248, His-2247, Thr-2245 for AZD8055. The binding pattern of both inhibitors was slightly different, responsible for better pharmacokinetic profile of AZD2014 and 5 fold increase in efficacy of AZD8055. The binding energy of best docking score for AZD8055 was -8.0 kcal/mol however AZD20144 showed best binding affinity at -8.2kcal/mol (RMSD l.b. 0.908, RMSD u.b. 1.075). Highly specific, less toxic and potent inhibitors can be designed or optimized based upon the docking results.

Marine-Derived Natural Products as ATP-Competitive mTOR Kinase Inhibitors for Cancer Therapeutics

“…The structure-based pharmacophore and MD analysis of the mTOR-PP242 crystal structure revealed that the inhibitor targets key residues Asp2195, Gly2238 and Val2240 via hydrogen bonds entailing essential pharmacophoric features including HBD and HBA ( Figure 1 B and Figure S2A ). It has been elucidated in previous studies that hydrogen bonds with Asp2195 and Val2240 are indispensable for mTOR inhibitory activity [ 50 , 51 , 52 , 53 , 54 , 55 , 56 ]. In the current study, Hit1 was observed to retain the hydrogen bonding interaction with Asp2195 ( Table 3 , Figure 4 A), while Hit4 interaction with both residues was preserved even after 30 ns of production simulation run ( Table 3 , Figure 4 D).…”

“…In the current study, Hit1 was observed to retain the hydrogen bonding interaction with Asp2195 ( Table 3 , Figure 4 A), while Hit4 interaction with both residues was preserved even after 30 ns of production simulation run ( Table 3 , Figure 4 D). Additionally, our hits formed hydrogen bonds with catalytic hydrophilic residue Asp2357 of the mTOR ATP-binding site which offers a level of specificity for our hits towards mTOR than PI3K ( Figure 4 ) [ 51 , 52 , 53 , 54 , 55 ]. The compound Hit2 also formed additional hydrogen bonds with residues Lys2187 and Thr2245 ( Figure 4 B) and interactions with these residues were also reported in previously published studies [ 22 , 51 , 52 , 55 ].…”

“…Additionally, our hits formed hydrogen bonds with catalytic hydrophilic residue Asp2357 of the mTOR ATP-binding site which offers a level of specificity for our hits towards mTOR than PI3K ( Figure 4 ) [ 51 , 52 , 53 , 54 , 55 ]. The compound Hit2 also formed additional hydrogen bonds with residues Lys2187 and Thr2245 ( Figure 4 B) and interactions with these residues were also reported in previously published studies [ 22 , 51 , 52 , 55 ]. A recent study reported natural products as mTOR ATP-binding site and rapamycin binding site inhibitors derived from three databases—Marine Natural Products Library, SuperNatural II and ZINC natural products—and also provided experimental evidence against mTOR for eleven compounds [ 23 ].…”