Docking And MD Simulations On Protein Arginine Deiminase 4 Inhibitors-benzoyl Arginine Amide Derivatives

Protein Arginine Deiminase 4 has been considered to be the target to cure the rheumatoid arthritis recently. As benzoyl arginine compounds have high affinity to interact with PAD4, they can be used as the drug leads. The interaction model between benzoyl arginine compounds and PAD4 was established based on the interacting modes of PAD4- benzoyl-L-arginine amide in the crystal structure. The results indicate seven hydrogen bonds formed between BAA and residues Arg374, Asp350, Asp473 and Arg639 in PAD4. In addition, residues Arg372,His471 and Cys645 directly participate in the interaction between BAA and PAD4.To obtain better drug leads, BAA were designed based on the isostere theory, and a conformation database consisting of 82 isostere analogs was built. Then the ligands were docked into the ligand binding pocket of the PAD4 to obtain the better leads based on model that had been built above. As a result, eight compounds which possessed higher docking score than the BAA compounds. Among the eight compounds, compound1 and compound2 were obtained by the substitution of the hydrogen in the No.6 of the phenyl on BAA compound using hydroxyl and Cl atom respectively; compound3 and compound4 were obtained by substitution of the C atoms in the position 10 and 11 of the Cαbackbone using N atoms separately; compound5 was obtained by the substitution of the N atom in No.17 using CONH; compound6, compound7 and compound8 were obtained by the phenyl using corresponding heterocyclic isosteres respectively. The higher docking score of the eight compounds attributes to three reasons: more reasonable hydrogen binding, more powerful electrostatic interaction and stronger hydrophobic interaction.Finally, two compounds with high Docking score among the eight compounds were selected and they were merged into the ligand binding pocket of PAD4. Then molecular dynamic simulation was performed on these two complexes to obtain more details of the binding modes between the ligands and the receptor. The final result indicated there was no substantial conformation perturbation of the residues in the ligand binding site. This result indicates the stability of complexes between the newly designed compounds and the PAD4 receptor.