In silico results of ϰ-Opioid receptor antagonists as ligands for the second bromodomain of the Pleckstrin Homology Domain Interacting Protein

Abstract

AbstractPleckstrin Homology Domain Interacting Protein (PHIP) is a member of the BRWD1-3 Family (Bromodomain and WD repeat-containing proteins). PHIP (BRWD2, WDR11) contains a WD40 repeat (methyl-lysine binder) and 2 bromodomains (acetyl-lysine binder). It was discovered through interactions with the pleckstrin homology domain of Insulin Receptor Signalling (IRS) proteins and has been shown to mediate transcriptional responses in pancreatic islet cells and postnatal growth. An initial hit for the second bromodomain of PHIP (PHIP(2)) was discovered in 2012, with consecutive research yielding a candidate with a binding affinity of 68μM. PHIP(2) is an atypical category III bromodomain with a threonine (THR1396) where an asparagine residue would usually be. In the standard case, this pocket holds four water molecules, but in the case of PHIP(2), there is room for one extra water molecule - also known as “PHIP water”, able to mediate interaction between THR1396 and the typical water network at the back of the binding pocket. We present first ever results of two ϰ-Opioid receptor (KOR) antagonists with distinct pharmacophores having an estimated binding affinity in the nM to μM range, as well as higher binding affinities for every currently discovered PHIP(2) ligand towards KOR. Finally, we also demonstrate selectivity of LY-255582 and LY-2459989 towards PHIP(2) over other bromodomains.