4.9. Molecular Docking Simulation of PTP1B Inhibition

The X-ray crystallographic structure of PTP1B complexed with its selective inhibitor 3-(3,5-dibromo-4-hydroxy-benzoyl)-2-ethyl-benzofuran-6-sulfonic acid (4-sulfamoyl-phenyl)-amide (compound 2) (PDB ID: 1T49) and the 3D structure of its catalytic inhibitor 3-({5-[(N-acetyl-3-{4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-1-naphthyl}-l-alanyl)amino]pentyl}oxy)-2-naphthoic acid (compound 23) were obtained from the RCSB Protein Data Bank [67,68] website. The resolution of the crystal structure was 1.9 Å [69], and the PubChem Compound (NCBI) CID was 447410. The bound PTP1B inhibitor and water molecules were removed from the structure for the docking simulation using Accelrys Discovery Studio 4.1 software (Accelrys, Inc. San Diego, CA, USA). The 3D structures of icaritin and icariside II were obtained from PubChem Compound (NCBI), corresponding to compound CIDs of 5318980 and 44587252, respectively, and protonated (pH 7.0) using the MarvinSketch program (ChemAxon, Budapest, Hungary). Automated docking simulation was performed using AutoDock Tool (ADT) to assess the appropriate binding orientations and conformations of the PTP1B with the different compounds. A Lamarkian genetic algorithm method implemented in AutoDock 4.2 was employed. For docking calculations, Gasteiger charges were added by default, the rotatable bonds were set by the ADTs, and all torsions were allowed to rotate. Grid maps were generated by the Autogrid program; the grid box size was 80 × 80 × 80 and had a default spacing of 0.375 Å. The X, Y, and Z centers were 51, 19.034, and 14.048, respectively. The docking protocol for rigid and flexible ligand docking consisted of 10 independent genetic algorithms, whereas ADT default settings were used for the other parameters. Binding PTP1B residues and their corresponding binding affinity scores were regarded as the best molecular interactions. The results were analyzed using UCSF Chimera [70], while the hydrogen bonds and van der Waals interaction residues were visualized by Ligplot 1.4.5.