title: Aryl Sulfonamide Inhibitors of Insulin-Regulated Aminopeptidase Enhance Spine Density in Primary Hippocampal Neuron Cultures.
abstract: The zinc metallopeptidase insulin regulated aminopeptidase (IRAP), which is highly expressed in the hippocampus and other brain regions associated with cognitive function, has been identified as a high-affinity binding site of the hexapeptide angiotensin IV (Ang IV). This hexapeptide is thought to facilitate learning and memory by binding to the catalytic site of IRAP to inhibit its enzymatic activity. In support of this hypothesis, low molecular weight, nonpeptide specific inhibitors of IRAP have been shown to enhance memory in rodent models. Recently, it was demonstrated that linear and macrocyclic Ang IV-derived peptides can alter the shape and increase the number of dendritic spines in hippocampal cultures, properties associated with enhanced cognitive performance. After screening a library of 10 500 drug-like substances for their ability to inhibit IRAP, we identified a series of low molecular weight aryl sulfonamides, which exhibit no structural similarity to Ang IV, as moderately potent IRAP inhibitors. A structural and biological characterization of three of these aryl sulfonamides was performed. Their binding modes to human IRAP were explored by docking calculations combined with molecular dynamics simulations and binding affinity estimations using the linear interaction energy method. Two alternative binding modes emerged from this analysis, both of which correctly rank the ligands according to their experimental binding affinities for this series of compounds. Finally, we show that two of these drug-like IRAP inhibitors can alter dendritic spine morphology and increase spine density in primary cultures of hippocampal neurons.
authors: Shanti
authors: S
authors: Diwakarla
authors: Erik
authors: E
authors: Nylander
authors: Alfhild
authors: A
authors: Grönbladh
authors: Sudarsana Reddy
authors: SR
authors: Vanga
authors: Yasmin
authors: Y
authors: Shamsudin
authors: Hugo
authors: H
authors: Gutiérrez-de-Terán
authors: Jonas
authors: J
authors: Sävmarker
authors: Biomedicine Discovery Institute, Department of Physiology, Monash University , Clayton, Victoria 3800, Australia.
authors: Leelee
authors: L
authors: Ng
authors: Biomedicine Discovery Institute, Department of Physiology, Monash University , Clayton, Victoria 3800, Australia.
authors: Vi
authors: V
authors: Pham
authors: Chemical Biology Consortium Sweden, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medicinal Biochemistry and Biophysics, Karolinska Institute , 171 77 Solna, Sweden.
authors: Thomas
authors: T
authors: Lundbäck
authors: Chemical Biology Consortium Sweden, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medicinal Biochemistry and Biophysics, Karolinska Institute , 171 77 Solna, Sweden.
authors: Annika
authors: A
authors: Jenmalm-Jensen
authors: Richard
authors: R
authors: Svensson
authors: Per
authors: P
authors: Artursson
authors: Sofia
authors: S
authors: Zelleroth
authors: Karin
authors: K
authors: Engen
authors: Ulrika
authors: U
authors: Rosenström
authors: Mats
authors: M
authors: Larhed
authors: Johan
authors: J
authors: Åqvist
authors: Biomedicine Discovery Institute, Department of Physiology, Monash University , Clayton, Victoria 3800, Australia.
authors: Siew Yeen
authors: SY
authors: Chai
authors: Mathias
authors: M
authors: Hallberg
mesh_terms: D000818:Animals; D018826:CD13 Antigens / Q000378:metabolism; D002478:Cells, Cultured; D018920:Coculture Techniques; D010122:Cystinyl Aminopeptidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D049229:Dendritic Spines / Q000187:drug effects* / Q000201:enzymology; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006624:Hippocampus / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D011485:Protein Binding; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000235:genetics; D013449:Sulfonamides / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D013449:Sulfonamides; D004851:Epoxide Hydrolases; D018826:CD13 Antigens; D010122:Cystinyl Aminopeptidase; C105964:leucyl-cystinyl aminopeptidase; C043134:leukotriene A4 hydrolase
keywords: Insulin-regulated aminopeptidase; aryl sulfonamides; dendritic spines; hippocampal neurons; ligand interaction energy simulations; molecular dynamics