Identification of Nerve Growth Factor (NGF) Receptor Modulators for Nerve Regeneration

Abstract

The physiological role of the neurotrophin nerve growth factor (NGF) has been characterized, since its discovery in the 1950s, first in the sensory and autonomic nervous system, then in central nervous, endocrine and immune systems. The biological function of the NGF is the maintenance and survival of the peripheral and central nervous systems, which makes them of great therapeutic interest for the treatment of a number of neurodegenerative diseases. Identifying the ligands which can enhance the effect of this growth factor can be very vital for using it as a pharmacological tool in the treatment of various CNS diseases like the Alzheimer’s Disease, Parkinson’s Disease, Glaucoma and advanced optic nerve atrophy and various peripheral neuropathies. The property of the NGF to promote neuronal regeneration can also be applied in neural tissue engineering applications. Molecular docking was performed by Autodock4.2 using Lamarckian Genetic Algorithm to identify the ligands with high binding affinity with the NGF receptor TrkA. The best docked ligands were further analyzed for their potential as drug candidates by predicting their ADME properties using online PreADMET tool. From the combined analysis of molecular docking and ADME properties, a group of ligands having similar structure were further investigated to reveal that their similar structure led to their similar binding affinities with the NGFR. Quantitative Structure-Analysis Relationship (QSAR) models were studied using oleanolic acid as base structure, and 2D and 3D QSAR mathematical models were generated by using VlifeMDS (Version 4.3) to predict the activities of new analogs. These models can also be used to design new analogs with better activities by modulating the structure based on the results obtained.