TITLE:
Affinity Crosslinking of Y1036 to Nerve Growth Factor Identifies Pharmacological Targeting Domain for Small Molecule Neurotrophin Antagonists
AUTHORS:
Joseph K. Eibl, Zouleika Abdallah, Allison E. Kennedy, John A. Scott, Gregory M. Ross
KEYWORDS:
NGF; BDNF; Inhibitor; Antagonist; Pain
JOURNAL NAME:
Neuroscience and Medicine,
Vol.4 No.4,
December
27,
2013
ABSTRACT: Classically, small molecule
antagonists have targeted membrane bound receptors and intracellular enzyme
targets. While this drug discovery strategy is extremely successful, the number
of new chemical entities in the pharmaceutical pipeline is diminishing and
complementary strategies are in need. A particularly attractive therapeutic
strategy is to neutralize soluble signalling proteins using small molecules.
Small molecule-based technologies have the potential
to sufficiently alter the molecular topology of a given ligand and inhibit
ligand/receptor interactions—effectively neutralizing the ligand’s signalling capacity. Recent technical advances in the
field of structural biology have enabled the elucidation of ligand/receptor complexes
at atomic resolution enabling a detailed appreciation of the molecular interactions
governing ligand-mediated receptor activation. Exploiting molecular modeling
techniques to study these signalling complexes allows for a paradigm shift from “receptorcentric” to “ligandcentric” screening strategies. Nerve growth factor (NGF) is a prototypical protein
signalling ligand, which binds two receptors, TrkA and p75NTR. We
first explore the molecular landscape governing the ligand/receptor
interactions of NGF/TrkA and NGF/p75 structures. Next, we use the recently
reported NGF neutralizing small-molecule, Y1036, as an affinity probe to
determine residues in proximity to the pharmacological targeting domain of NGF
and perform theoretical docking experiments to predict the residues which
comprise distinct pharmacological targeting domains on the surface of NGF. Exploiting
such strategies may facilitate “ligandcentric” drug discovery and could further the
development of a trophic-factor-selective compound such as a BDNF-selective
antagonist.