Molecular docking approaches in identification of High affinity inhibitors of Human SMO receptor

Abstract

Inappropriate activation of the Hh signaling pathway has been implicated in the development of several types of cancers including prostate, lung, pancreas, breast, brain and skin. Present study identified the binding affinities of eight established inhibitors viz., Cyclopamine, Saridegib, Itraconazole, LDE-225, TAK-441, BMS-833923 (XL139), PF-04449913 and Vismodegib targeting SMO receptor - a candidate protein involved in hedgehog pathway and sought to identify the best amongst the established inhibitors through by molecular docking. Exelxis® BMS 833923 (XL 139) demonstrated superior binding affinity aided by MolDock scoring docking algorithm. Further BMS 833923 (XL 139) was evaluated for pharmacophoric features which revealed appreciable ligand receptor interactions.

Keywords: BMS 833923; Hedgehog Pathway; SMO Inhibitors; Tumorogenesis.

Figure 1

KS_601 (green) bound to SMO in the inhibitory site

Figure 2

BMS 833923 (XL 139) and its interactions with SMO

Figure 3

Hydrogen bond interactions of BMS 833923 (XL 139) with SMO

Figure 4

Electrostatic interactions of BMS 833923 (XL 139) with SMO

Figure 5

Hydrophobic interactions of BMS 833923 (XL 139) with SMO

Figure 6

Solvent accessible surface area analysis of BMS 833923 (XL 139) with SMO