Discovery of Novel Analgesic Agents Targeting Neuropathic Pain: Computer-Aided Drug Design

Background: Neurotrophin family combines nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (N3) and neurotrophin 4 (N4). p75 receptor is the target for these neurotrophins. They bind to it by tropomyosin related kinase enzyme Trk with different affinity. Trk enzyme is classified into TrkA, TrkB and TrkC with different selectivity to neurotrophins family. NGF signals preferentially through TrkA, BNDF and N4 through TrkB, and N3 through TrkC. These neurotrophins have been found to be involved in pathophysiology of neuropathic pain. Material and Method: Molecular docking approach was used to conduct this study. Prior to start docking procedure, some modifications were made including removal of water from the receptor, application of energy minimization and Lipinski rule of five to the ligands. Toxicity studies, p-glycoprotein and human intestinal absorption were studied for the docked ligands. Result: 28 ligands of FDA approved drugs and 72 non-FDA approved ligands have shown high affinity to TrkA enzyme with different energies and hence are possible to be active against neuropathic pain. These 28 ligands of FDA approved drugs and 72 ligands of non-FDA approved drugs have declined to 10 ligands and 2 ligands respectively after studying toxicity, p-glycoprotein substrate, human intestinal absorption and hepatotoxicity. The least energy was consumed was -40.8985 by the FDA-approved drug N-Hydroxy-N'-phenyloctanediamide. Conclusion: The docked ligands were assumed to possess therapeutic activity against neuropathic pain based on their affinity to TrkA enzyme.