RT Journal Article
SR Electronic
T1 Binding to and Inhibition of Insulin-Regulated Aminopeptidase (IRAP) by Macrocyclic Disulfides Enhances Spine Density
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.115.102533
DO 10.1124/mol.115.102533
A1 Diwakarla, Shanti
A1 Nylander, Erik
A1 Gronbladh, Alfhild
A1 Vanga, Sudarsana Reddy
A1 Khan, Yasmin Shamsudin
A1 Gutierrez-de-Teran, Hugo
A1 Ng, Leelee
A1 Pham, Vi
A1 Savmarker, Jonas
A1 Lundback, Thomas
A1 Jenmalm-Jensen, Annika
A1 Andersson, Hanna
A1 Engen, Karin
A1 Rosenstrom, Ulrika
A1 Larhed, Mats
A1 Aqvist, Johan
A1 Chai, Siew Yeen
A1 Hallberg, Mathias
YR 2016
UL http://molpharm.aspetjournals.org/content/early/2016/01/14/mol.115.102533.abstract
AB Angiotensin IV (Ang IV) and related peptide analogues, as well as non-peptide inhibitors of insulin-regulated aminopeptidase (IRAP), have previously been shown to enhance memory and cognition in animal models. Furthermore, the endogenous IRAP substrates oxytocin and vasopressin are known to facilitate learning and memory. In this study, the two recently synthesized 13-membered macrocylic competitive IRAP inhibitors HA08 and HA09, which were designed to mimic the N-terminal of oxytocin and vasopressin, were assessed and compared based on their ability to bind to the IRAP active site, and alter dendritic spine density in rat hippocampal primary cultures. The binding modes of the IRAP inhibitors HA08, HA09 and of Ang IV in either the extended or γ-turn conformation at the C-terminal to human IRAP were predicted by docking and molecular dynamics (MD) simulations. The binding free energies calculated with the linear interaction energy (LIE) method, which are in excellent agreement with experimental data and simulations, have been used to explain the differences in activities of the IRAP inhibitors, both of which are structurally very similar, but differ only with regard to one stereogenic center. In addition, we show that HA08, which is 100-fold more potent than the epimer HA09, can enhance dendritic spine number and alter morphology, a process associated with memory facilitation. Therefore, HA08, one of the most potent IRAP inhibitors known today, may serve as a suitable starting point for medicinal chemistry programs aided by MD simulations aimed at discovering more drug-like cognitive enhancers acting via augmenting synaptic plasticity.