Identification of novel pyrazoloquinazolinecarboxilate analogues to inhibit nerve growth factor in vitro

Nerve growth factor inhibitor with novel‐binding domain demonstrates nanomolar efficacy in both cell‐based and cell‐free assay systems

“…Alternatively Y1036 has been described to bind at the neurotrophin hydrophobic interface, the region conserved among all neurtrophin family members, and therefore loses the specificity for NGF (Eibl et al. ).…”

“…This loop region of NGF has the highest degree of variance among all the neurotrophins and is responsible for the selectivity in receptor selection among the neurotrophin family members. Alternatively Y1036 has been described to bind at the neurotrophin hydrophobic interface, the region conserved among all neurtrophin family members, and therefore loses the specificity for NGF (Eibl et al 2013b).…”

A Surface Plasmon Resonance Spectroscopy Method for Characterizing Small-Molecule Binding to Nerve Growth Factor

“…A 2:1 stoichiometry (two small molecules to one NGF dimer) is hypothesized, which confirms previous work with molecular modeling techniques. 8,9,11 Small molecules can bind to proteins at a relatively low affinity to nonspecific sites as well as to a high affinity at specific sites, which can be measured using a two-site affinity model. This model groups together the low affinity as one weak binding site that provides a much more accurate K D value for the high-affinity site, which is usually the site of interest.…”

“…Using an approach to inhibiting NGF with the use of small molecules may have significant pharmacological, practical, and economic advantages over monoclonal antibodies. Small molecules such as ALE 0540, 7 PD 90780, 8 PQC 083, 9 Ro 08-2750, 10 and Y1036 11 have previously demonstrated an ability to inhibit NGF activity in vitro, and several of these have been suggested to bind the ligand NGF rather than the receptor.…”

“…13 The structure of NGF, proposed by McDonald and colleagues, describes a 118-amino-acid sequence that forms a monomer with four distinct loop regions and two β-pleated sheet strands. 13 Molecular modeling of PD 90780 and PQC 083 binding to NGF suggest a binding site at the loop I-loop IV cleft of NGF, 8,9 which would suggest a 2:1 stoichiometry (two small molecules to one NGF dimer). Originally, ALE 0540 was thought to bind to the binding sites on TrkA and p75 receptors 7 (rather than to NGF), and Ro 08-2750 was suggested to inhibit NGF at the hydrophobic dimer interface.…”