PT  - JOURNAL ARTICLE
AU  - Shanti Diwakarla
AU  - Erik Nylander
AU  - Alfhild Gronbladh
AU  - Sudarsana Reddy Vanga
AU  - Yasmin Shamsudin Khan
AU  - Hugo Gutierrez-de-Teran
AU  - Leelee Ng
AU  - Vi Pham
AU  - Jonas Savmarker
AU  - Thomas Lundback
AU  - Annika Jenmalm-Jensen
AU  - Hanna Andersson
AU  - Karin Engen
AU  - Ulrika Rosenstrom
AU  - Mats Larhed
AU  - Johan Aqvist
AU  - Siew Yeen Chai
AU  - Mathias Hallberg
TI  - Binding to and Inhibition of Insulin-Regulated Aminopeptidase (IRAP) by Macrocyclic Disulfides Enhances Spine Density
AID  - 10.1124/mol.115.102533
DP  - 2016 Jan 01
TA  - Molecular Pharmacology
PG  - mol.115.102533
4099  - http://molpharm.aspetjournals.org/content/early/2016/01/14/mol.115.102533.short
4100  - http://molpharm.aspetjournals.org/content/early/2016/01/14/mol.115.102533.full
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.