Open AccessNerve growth factor inhibitor with novel‐binding domain demonstrates nanomolar efficacy in both cell‐based and cell‐free assay systems
Author(s) -
Kennedy Allison E.,
Laamanen Corey A.,
Ross Mitchell S.,
Vohra Rahul,
Boreham Douglas R.,
Scott John A.,
Ross Gregory M.
Publication year - 2017
Publication title -
pharmacology research and perspectives
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.975
H-Index - 27
ISSN - 2052-1707
DOI - 10.1002/prp2.339
Subject(s) - nerve growth factor , neurotrophin , tropomyosin receptor kinase a , diabetic neuropathy , pharmacology , growth factor , population , chemistry , medicine , neuroscience , biology , endocrinology , receptor , diabetes mellitus , environmental health
Nerve growth factor ( NGF ), a member of the neurotrophin family, is known to regulate the development and survival of a select population of neurons through the binding and activation of the TrkA receptor. Elevated levels of NGF have been associated with painful pathologies such as diabetic neuropathy and fibromyalgia. However, completely inhibiting the NGF signal could hold significant side effects, such as those observed in a genetic condition called congenital insensitivity to pain and anhidrosis ( CIPA ). Previous methods of screening for NGF ‐inhibitors used labeling techniques which have the potential to alter molecular interactions. SPR spectroscopy and NGF ‐dependent cellular assays were utilized to identify a novel NGF ‐inhibitor, BVNP ‐0197 ( IC 50 = 90 nmol/L), the first NGF ‐inhibitor described with a high nanomolar NGF inhibition efficiency. The present study utilizes molecular modeling flexible docking to identify a novel binding domain in the loop II / IV cleft of NGF .