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It has been demonstrated that inhibition of IRAP by angiotensin IV (Ang IV) and other peptides, as well as more druglike inhibitors, improves cognition in several rodent models. We recently reported a series of aryl sulfonamides as small-molecule IRAP inhibitors and a promising scaffold for pharmacological intervention. We have now expanded with a number of derivatives, report their stability in liver microsomes, and characterize the activity of the whole series in a new assay performed on recombinant human IRAP. Several compounds, such as the new fluorinated derivative 29, present submicromolar affinity and high metabolic stability. Starting from the two binding modes previously proposed for the sulfonamide scaffold, we systematically performed molecular dynamics simulations and binding affinity estimation with the linear interaction energy method for the full compound series. The significant agreement with experimental affinities suggests one of the binding modes, which was further confirmed by the excellent correlation for binding affinity differences between the selected pair of compounds obtained by rigorous free energy perturbation calculations. The new experimental data and the computationally derived structure\u2013activity relationship of the sulfonamide series provide valuable information for further lead optimization of novel IRAP inhibitors.<\/jats:p>","DOI":"10.1021\/acsomega.8b00595","type":"journal-article","created":{"date-parts":[[2018,4,25]],"date-time":"2018-04-25T06:30:22Z","timestamp":1524637822000},"page":"4509-4521","source":"Crossref","is-referenced-by-count":22,"title":["Structural Basis of Inhibition of Human Insulin-Regulated\nAminopeptidase (IRAP) by Aryl Sulfonamides"],"prefix":"10.1021","volume":"3","author":[{"given":"Sudarsana Reddy","family":"Vanga","sequence":"first","affiliation":[{"name":"Uppsala University , Box 596, , ,","place":["Uppsala, Sweden, SE-751 24"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonas","family":"Sa\u0308vmarker","sequence":"additional","affiliation":[{"name":"Uppsala University, BMC , , ,","place":["Uppsala, Sweden, SE-751 24"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leelee","family":"Ng","sequence":"additional","affiliation":[{"name":"Monash University , , , ,","place":["Clayton, Victoria, Australia, 3800"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6258-0635","authenticated-orcid":true,"given":"Mats","family":"Larhed","sequence":"additional","affiliation":[{"name":"Uppsala University, BMC , , ,","place":["Uppsala, Sweden, SE-751 24"]},{"name":"Uppsala University, BMC , , ,","place":["Uppsala, Sweden, SE-751 24"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathias","family":"Hallberg","sequence":"additional","affiliation":[{"name":"Uppsala University, BMC , , ,","place":["Uppsala, Sweden, SE-751 23"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2091-0610","authenticated-orcid":true,"given":"Johan","family":"\u00c5qvist","sequence":"additional","affiliation":[{"name":"Uppsala University , Box 596, , ,","place":["Uppsala, Sweden, SE-751 24"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anders","family":"Hallberg","sequence":"additional","affiliation":[{"name":"Uppsala University, BMC , , ,","place":["Uppsala, Sweden, SE-751 24"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siew Yeen","family":"Chai","sequence":"additional","affiliation":[{"name":"Monash University , , , ,","place":["Clayton, Victoria, Australia, 3800"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0459-3491","authenticated-orcid":true,"given":"Hugo","family":"Gutie\u0301rrez-de-Tera\u0301n","sequence":"additional","affiliation":[{"name":"Uppsala University , Box 596, , ,","place":["Uppsala, Sweden, SE-751 24"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2018,4,25]]},"reference":[{"key":"2026090407121661900_cit1","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1016\/j.bbr.2004.02.012","article-title":"Attenuation of Scopolamine-Induced Learning Deficits\nby LVV-Hemorphin-7 in Rats in the Passive Avoidance and Water Maze\nParadigms","volume":"154","author":"Albiston","year":"2004","journal-title":"Behav. 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Endocrinol."},{"key":"2026090407121661900_cit26","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1007\/s10741-007-9062-x","article-title":"Involvement\nof Insulin-Regulated Aminopeptidase in the Effects of the Renin\u2013angiotensin\nFragment Angiotensin IV: A Review","volume":"13","author":"Stragier","year":"2008","journal-title":"Heart Failure\nRev."},{"key":"2026090407121661900_cit27","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2202-9-S2-S14","article-title":"Development\nof Cognitive Enhancers\nBased on Inhibition of Insulin-Regulated Aminopeptidase","volume":"9","author":"Chai","year":"2008","journal-title":"BMC Neurosci."},{"key":"2026090407121661900_cit28","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1358\/dnp.2009.22.3.1325032","article-title":"Targeting\nthe Insulin-Regulated Aminopeptidase\/AT4 Receptor for Cognitive Disorders","volume":"22","author":"Hallberg","year":"2009","journal-title":"Drug News Perspect."},{"key":"2026090407121661900_cit29","doi-asserted-by":"publisher","first-page":"859","DOI":"10.1038\/nrd938","article-title":"Therapeutic\nStrategies for Alzheimer\u2019s Disease","volume":"1","author":"Wolfe","year":"2002","journal-title":"Nat.\nRev. 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Chem."},{"key":"2026090407121661900_cit61","unstructured":"The\nPyMOL Molecular Graphics System, version 1.3; Schro\u0308dinger, LLC., 2010."},{"key":"2026090407121661900_cit62","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1016\/S1093-3263(98)80006-5","article-title":"Q: A Molecular Dynamics\nProgram for Free Energy Calculations and Empirical Valence Bond Simulations\nin Biomolecular Systems","volume":"16","author":"Marelius","year":"1998","journal-title":"J. Mol. Graphics Modell."},{"key":"2026090407121661900_cit63","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1003585","article-title":"Computational\nPrediction of Alanine Scanning and Ligand Binding Energetics in G-Protein\nCoupled Receptors","volume":"10","author":"Boukharta","year":"2014","journal-title":"PLoS Comput. Biol."},{"key":"2026090407121661900_cit64","doi-asserted-by":"publisher","first-page":"7283","DOI":"10.1021\/acs.biochem.5b01024","article-title":"Origin of the Enigmatic Stepwise Tight-Binding Inhibition\nof Cyclooxygenase-1","volume":"54","author":"Shamsudin Khan","year":"2015","journal-title":"Biochemistry"},{"key":"2026090407121661900_cit65","doi-asserted-by":"publisher","first-page":"11225","DOI":"10.1021\/ja9621760","article-title":"Development\nand Testing of the OPLS\nAll-Atom Force Field on Conformational Energetics and Properties of\nOrganic Liquids","volume":"118","author":"Jorgensen","year":"1996","journal-title":"J. Am. Chem. Soc."},{"key":"2026090407121661900_cit66","doi-asserted-by":"publisher","first-page":"926","DOI":"10.1063\/1.445869","article-title":"Comparison\nof Simple Potential Functions for Simulating Liquid Water","volume":"79","author":"Jorgensen","year":"1983","journal-title":"J. Chem. Phys."},{"key":"2026090407121661900_cit67","doi-asserted-by":"publisher","first-page":"3647","DOI":"10.1063\/1.456845","article-title":"A Surface Constrained\nAll-atom Solvent Model for Effective\nSimulations of Polar Solutions","volume":"91","author":"King","year":"1989","journal-title":"J. Chem. Phys."},{"key":"2026090407121661900_cit68","doi-asserted-by":"publisher","first-page":"3100","DOI":"10.1063\/1.462997","article-title":"A Local Reaction Field Method for Fast Evaluation of\nLong-range Electrostatic Interactions in Molecular Simulations","volume":"97","author":"Lee","year":"1992","journal-title":"J. Chem. Phys."},{"key":"2026090407121661900_cit69","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1016\/0021-9991(77)90098-5","article-title":"Numerical\nIntegration of the Cartesian\nEquations of Motion of a System with Constraints: Molecular Dynamics\nof N-Alkanes","volume":"23","author":"Ryckaert","year":"1977","journal-title":"J. Comput. Phys."},{"key":"2026090407121661900_cit70","doi-asserted-by":"publisher","first-page":"1242","DOI":"10.1002\/jcc.20047","article-title":"Binding Affinity\nPrediction with\nDifferent Force Fields: Examination of the Linear Interaction Energy\nMethod","volume":"25","author":"Almlo\u0308f","year":"2004","journal-title":"J. Comput. Chem."},{"key":"2026090407121661900_cit71","doi-asserted-by":"publisher","first-page":"2162","DOI":"10.1021\/ct700106b","article-title":"Improving the Accuracy of the Linear\nInteraction Energy Method for Solvation Free Energies","volume":"3","author":"Almlo\u0308f","year":"2007","journal-title":"J. Chem. 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