{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T18:24:30Z","timestamp":1788805470691,"version":"build-2803163510"},"reference-count":127,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,22]],"date-time":"2025-12-22T00:00:00Z","timestamp":1766361600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>The renin\u2013angiotensin\u2013aldosterone system (RAAS) is essential for controlling blood pressure and maintaining fluid balance, driving significant structural changes throughout the cardiovascular system, including the heart and blood vessels. As a result, the RAAS is a key therapeutic target for various chronic cardiovascular diseases, ranging from arterial hypertension (AH) to heart failure (HF). In this review, one of our objectives is to describe the new evidence over the last 4 years regarding the RAAS. Moreover, we pay attention to the structure and function of the angiotensin II type 1 receptor (AT1R) and its role in hypertension, as well as define its active site. Later, we discuss the most potent, selective inhibitors of AT1 receptors, based on in vitro and in vivo experiments, from 2020 to 2024. Large peptide molecules, small non-peptide-like molecules, and sartan derivatives are analyzed. The low IC50 values of the entities that do not resemble sartans showcase the vast chemical space that can be explored for the creation of more potent antihypertensive medications. We have also employed computational chemistry tools in order to identify key molecular interactions between the compounds of the literature studied in order to elucidate the underlying reasons why these different molecules exhibit variations in their binding energies and overall potency.<\/jats:p>","DOI":"10.3390\/biom16010020","type":"journal-article","created":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T10:57:18Z","timestamp":1766487438000},"page":"20","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Structural and Computational Insights into the Angiotensin II Type 1 Receptor: Advances in Antagonist Design and Implications for Hypertension Therapy (2020\u20132024)"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-6144-6694","authenticated-orcid":false,"given":"Filippos Panteleimon","family":"Chatzipieris","sequence":"first","affiliation":[{"name":"Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, 15771 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-3805-6558","authenticated-orcid":false,"given":"Errikos","family":"Petsas","sequence":"additional","affiliation":[{"name":"Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, 15771 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2820-9338","authenticated-orcid":false,"given":"George","family":"Lambrinidis","sequence":"additional","affiliation":[{"name":"Division of Medicinal Chemistry, Department of Pharmacy, School of Health Sciences, National & Kapodistrian University of Athens, 15771 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5554-2964","authenticated-orcid":false,"given":"John M.","family":"Matsoukas","sequence":"additional","affiliation":[{"name":"Institute for Health and Sport, Victoria University, Melbourne, VIC 3030, Australia"},{"name":"Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada"},{"name":"NewDrug, P.C., Patras Science Park, 26504 Patras, Greece"},{"name":"Department of Chemistry, University of Patras, 26504 Patras, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5309-992X","authenticated-orcid":false,"given":"Thomas","family":"Mavromoustakos","sequence":"additional","affiliation":[{"name":"Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, 15771 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.tcm.2019.05.003","article-title":"Blood Pressure and the New ACC\/AHA Hypertension Guidelines","volume":"30","author":"Flack","year":"2020","journal-title":"Trends Cardiovasc. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"101622","DOI":"10.1016\/j.cpcardiol.2023.101622","article-title":"Global Cardiovascular Diseases Death Rate Prediction","volume":"48","author":"Gaidai","year":"2023","journal-title":"Curr. Probl. Cardiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1246","DOI":"10.1038\/s41440-024-01642-6","article-title":"Hypertension Facilitates Age-Related Diseases. Is Hypertension Associated with a Wide Variety of Diseases?","volume":"47","author":"Mogi","year":"2024","journal-title":"Hypertens. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1093\/eurjpc\/zwae281","article-title":"Global Burden of Cardiovascular Diseases: Projections from 2025 to 2050","volume":"32","author":"Chong","year":"2025","journal-title":"Eur. J. Prev. Cardiol."},{"key":"ref_5","first-page":"e347","article-title":"2025 Heart Disease and Stroke Statistics: A Report of US and Global Data From the American Heart Association","volume":"151","author":"Martin","year":"2025","journal-title":"Circulation"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e2160","DOI":"10.1097\/MD.0000000000002160","article-title":"High Blood Pressure and All-Cause and Cardiovascular Disease Mortalities in Community-Dwelling Older Adults","volume":"94","author":"Wu","year":"2015","journal-title":"Medicine"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1016\/j.amjhyper.2005.01.011","article-title":"A Summary of the Effects of Antihypertensive Medications on Measured Blood Pressure","volume":"18","author":"Wu","year":"2005","journal-title":"Am. J. Hypertens."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1161\/HYPERTENSIONAHA.109.129171","article-title":"Thiazide Effects and Adverse Effects: Insights From Molecular Genetics","volume":"54","author":"Ellison","year":"2009","journal-title":"Hypertension"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1851","DOI":"10.2147\/JMDH.S374887","article-title":"Calcium Channel Blocker Toxicity: A Practical Approach","volume":"15","author":"Alshaya","year":"2022","journal-title":"J. Multidiscip. Healthc."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e156","DOI":"10.1111\/j.1755-5922.2010.00258.x","article-title":"Hyperkalemia Associated with Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers","volume":"30","author":"Raebel","year":"2012","journal-title":"Cardiovasc. Ther."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1007\/s11886-020-01352-8","article-title":"Should Angiotensin-Converting Enzyme Inhibitors Ever Be Used for the Management of Hypertension?","volume":"22","author":"Turner","year":"2020","journal-title":"Curr. Cardiol. Rep."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1177\/019459989010300521","article-title":"Life-threatening Angioedema","volume":"103","author":"Barna","year":"1990","journal-title":"Otolaryngol. Head Neck Surg."},{"key":"ref_13","unstructured":"(2023). Side Effects of Antihypertensive Drugs. Side Effects of Drugs Annual, Elsevier."},{"key":"ref_14","first-page":"e54311","article-title":"A Comparative Study of the Safety and Efficacy Between Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers on the Management of Hypertension: A Systematic Review","volume":"16","author":"Peresuodei","year":"2024","journal-title":"Cureus"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1093\/ajhp\/57.13.1231","article-title":"Angiotensin II-Receptor Antagonists: An Overview","volume":"57","author":"Dina","year":"2000","journal-title":"Am. J. Health-Syst. Pharm."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1093\/ajhp\/58.8.671","article-title":"Angiotensin II-Receptor Blockers: Clinical Relevance and Therapeutic Role","volume":"58","author":"Rodgers","year":"2001","journal-title":"Am. J. Health-Syst. Pharm."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1007\/s11906-019-1001-4","article-title":"Arterial Hypertension, Aldosterone, and Atrial Fibrillation","volume":"21","author":"Seccia","year":"2019","journal-title":"Curr. Hypertens. Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.mcna.2016.08.017","article-title":"Local Renin Angiotensin Aldosterone Systems and Cardiovascular Diseases","volume":"101","year":"2017","journal-title":"Med. Clin. North Am."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1042\/CS20130436","article-title":"Angiotensin-(1\u20137) and Angiotensin-(1\u20139): Function in Cardiac and Vascular Remodelling","volume":"126","author":"McKinney","year":"2014","journal-title":"Clin. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2021","DOI":"10.1038\/s41440-022-01033-9","article-title":"Prorenin: What Are Its Functions?","volume":"45","author":"Senbonmatsu","year":"2022","journal-title":"Hypertens. Res."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Nandave, M. (2024). Introduction of Renin-Angiotensin-Aldosterone System (RAAS). Angiotensin-Converting Enzyme Inhibitors vs. Angiotensin Receptor Blockers, Springer Nature.","DOI":"10.1007\/978-981-97-7380-0"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"95","DOI":"10.3892\/ijmm.2021.4928","article-title":"Role of the Central Renin-angiotensin System in Hypertension (Review)","volume":"47","author":"Su","year":"2021","journal-title":"Int. J. Mol. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1016\/j.jchf.2022.06.005","article-title":"Angiotensinogen","volume":"10","author":"Kahlon","year":"2022","journal-title":"JACC Heart Fail."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1093\/ajh\/2.5.403","article-title":"Regulation of Angiotensinogen Gene","volume":"2","author":"Clauser","year":"1989","journal-title":"Am. J. Hypertens."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1038\/s41581-021-00414-6","article-title":"The Evolving Complexity of the Collecting Duct Renin\u2013Angiotensin System in Hypertension","volume":"17","author":"Prieto","year":"2021","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2115","DOI":"10.1161\/HYPERTENSIONAHA.122.18731","article-title":"Angiotensinogen Suppression: A New Tool to Treat Cardiovascular and Renal Disease","volume":"79","author":"Ye","year":"2022","journal-title":"Hypertension"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4239","DOI":"10.1021\/ja00992a059","article-title":"Synthesis of Human Angiotensin. I","volume":"89","author":"Aoyagi","year":"1967","journal-title":"J. Am. Chem. Soc."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1016\/0006-291X(81)90762-2","article-title":"The Amino Terminal Amino Acid Sequence of Human Angiotensinogen","volume":"99","author":"Tewksbury","year":"1981","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Jo, D.-M., Khan, F., Park, S.-K., Ko, S.-C., Kim, K.W., Yang, D., Kim, J.-Y., Oh, G.-W., Choi, G., and Lee, D.-S. (2024). From Sea to Lab: Angiotensin I-Converting Enzyme Inhibition by Marine Peptides\u2014Mechanisms and Applications. Mar. Drugs, 22.","DOI":"10.3390\/md22100449"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Santos, R.A.S. (2019). The Angiotensin-(1-7) Axis: Formation and Metabolism Pathways. Angiotensin-(1-7), Springer International Publishing.","DOI":"10.1007\/978-3-030-22696-1_1"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.cca.2021.10.029","article-title":"Angiotensin Converting Enzyme (ACE)","volume":"524","author":"Khurana","year":"2022","journal-title":"Clin. Chim. Acta"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"111257","DOI":"10.1016\/j.mce.2021.111257","article-title":"Novel Roles of the Renal Angiotensin-Converting Enzyme","volume":"529","author":"Giani","year":"2021","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Wong, M.K.-S. (2021). Angiotensin Converting Enzyme. Handbook of Hormones, Elsevier.","DOI":"10.1016\/B978-0-12-820649-2.00128-5"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"6","DOI":"10.2174\/1871530321666210212144511","article-title":"The Role of Angiotensin-Converting Enzyme in Immunity: SheddingLight on Experimental Findings","volume":"22","author":"Aghsaeifard","year":"2022","journal-title":"EMIDDT"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1046\/j.1432-1327.1998.2510448.x","article-title":"The Octapeptide Angiotensin II Adopts a Well-defined Structure in a Phospholipid Environment","volume":"251","author":"Carpenter","year":"1998","journal-title":"Eur. J. Biochem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"S31","DOI":"10.1016\/S0895-7061(99)00249-6","article-title":"Localization and Function of Angiotensin AT1 Receptors","volume":"13","author":"Allen","year":"2000","journal-title":"Am. J. Hypertens."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1042\/CS20110036","article-title":"Relative Affinity of Angiotensin Peptides and Novel Ligands at AT1 and AT2 Receptors","volume":"121","author":"Bosnyak","year":"2011","journal-title":"Clin. Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1080\/08037050310001057","article-title":"Angiotensin AT1\/AT2 Receptors: Regulation, Signalling and Function","volume":"12","author":"Kaschina","year":"2003","journal-title":"Blood Press."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"108975","DOI":"10.1016\/j.cbi.2020.108975","article-title":"Monotherapy of RAAS Blockers and Mobilization of Aldosterone: A Mechanistic Perspective Study in Kidney Disease","volume":"317","author":"Gupta","year":"2020","journal-title":"Chem. Biol. Interact."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1093\/ajh\/hpaa137","article-title":"Aldosterone, Inflammation, Immune System, and Hypertension","volume":"34","author":"Ferreira","year":"2021","journal-title":"Am. J. Hypertens."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Hall, J.E., Omoto, A.C.M., Wang, Z., Mouton, A., Li, X., and Hall, M.E. (2024). Pathophysiology of Hypertension. Hypertension, Elsevier.","DOI":"10.1016\/B978-0-323-88369-6.00005-0"},{"key":"ref_42","unstructured":"Prakash, Y.S. (2023). Aldosterone: Renal Action and Physiological Effects. Comprehensive Physiology, Wiley."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Bioletto, F., Bollati, M., Lopez, C., Arata, S., Procopio, M., Ponzetto, F., Ghigo, E., Maccario, M., and Parasiliti-Caprino, M. (2022). Primary Aldosteronism and Resistant Hypertension: A Pathophysiological Insight. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23094803"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Ferreira, N.S., Cau, S.B.A., Silva, M.A.B., Manzato, C.P., Mestriner, F.L.A.C., Matsumoto, T., Carneiro, F.S., and Tostes, R.C. (2015). Diabetes Impairs the Vascular Effects of Aldosterone Mediated by G Protein-Coupled Estrogen Receptor Activation. Front. Pharmacol., 6.","DOI":"10.3389\/fphar.2015.00034"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1159\/000345243","article-title":"Vascular Actions of Aldosterone","volume":"50","author":"Briet","year":"2013","journal-title":"J. Vasc. Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1161\/01.HYP.0000201443.63240.a7","article-title":"Effects of Aldosterone on the Vasculature","volume":"47","author":"Schiffrin","year":"2006","journal-title":"Hypertension"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Silva, M.A.B., Bruder-Nascimento, T., Cau, S.B.A., Lopes, R.A.M., Mestriner, F.L.A.C., Fais, R.S., Touyz, R.M., and Tostes, R.C. (2015). Spironolactone Treatment Attenuates Vascular Dysfunction in Type 2 Diabetic Mice by Decreasing Oxidative Stress and Restoring NO\/GC Signaling. Front. Physiol., 6.","DOI":"10.3389\/fphys.2015.00269"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1773","DOI":"10.1016\/S0002-9440(10)64454-9","article-title":"Aldosterone-Induced Inflammation in the Rat Heart","volume":"161","author":"Sun","year":"2002","journal-title":"Am. J. Pathol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"e638","DOI":"10.1210\/clinem\/dgad071","article-title":"Aldosterone Synthase Inhibitors and the Treatment of Essential Hypertension","volume":"108","year":"2023","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1093\/ndt\/gfs388","article-title":"Aldosterone Synthase Inhibition in Humans","volume":"28","author":"Azizi","year":"2013","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.1001\/jama.2023.16029","article-title":"Aldosterone Synthase Inhibition with Lorundrostat for Uncontrolled Hypertension: The Target-HTN Randomized Clinical Trial","volume":"330","author":"Laffin","year":"2023","journal-title":"JAMA"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1161\/HYPERTENSIONAHA.119.12675","article-title":"Evolution of a New Class of Antihypertensive Drugs: Targeting the Brain Renin-Angiotensin System","volume":"75","author":"Touyz","year":"2020","journal-title":"Hypertension"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1007\/s11906-005-0087-z","article-title":"Role of Angiotensin III in Hypertension","volume":"7","author":"Iturrioz","year":"2005","journal-title":"Curr. Sci. Inc."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"H218","DOI":"10.1152\/ajpheart.1979.237.2.H218","article-title":"Formation of Angiotensin III from [Des-Asp1]Angiotensin I in the Mesentric Vasculature","volume":"237","author":"Sexton","year":"1979","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1006\/frne.1995.1002","article-title":"The Angiotensin IV System: Functional Implications","volume":"16","author":"Wright","year":"1995","journal-title":"Front. Neuroendocrinol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1080\/10641963.2017.1377218","article-title":"Hypertension Regulating Angiotensin Peptides in the Pathobiology of Cardiovascular Disease","volume":"40","author":"Hussain","year":"2018","journal-title":"Clin. Exp. Hypertens."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1248\/bpb.27.761","article-title":"Role of the Insulin-Regulated Aminopeptidase IRAP in Insulin Action and Diabetes","volume":"27","author":"Keller","year":"2004","journal-title":"Biol. Pharm. Bull."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.1007\/s11357-020-00231-y","article-title":"Brain Angiotensin II and Angiotensin IV Receptors as Potential Alzheimer\u2019s Disease Therapeutic Targets","volume":"42","author":"Royea","year":"2020","journal-title":"GeroScience"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2728","DOI":"10.1007\/s00018-004-4246-1","article-title":"What\u2019s New in the Renin-Angiotensin System? The Angiotensin IV\/AT4 Receptor","volume":"61","author":"Chai","year":"2004","journal-title":"CMLS Cell. Mol. Life Sci."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Gard, P.R. (2008). Cognitive-Enhancing Effects of Angiotensin IV. BMC Neurosci., 9.","DOI":"10.1186\/1471-2202-9-S2-S15"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"639","DOI":"10.2174\/092986707780059571","article-title":"The Structure and Main Functions of Aminopeptidase N","volume":"14","author":"Luan","year":"2007","journal-title":"Curr. Med. Chem."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/S1535-6108(04)00025-X","article-title":"Aminopeptidase A Is a Functional Target in Angiogenic Blood Vessels","volume":"5","author":"Lahdenranta","year":"2004","journal-title":"Cancer Cell"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/S0165-0173(97)00019-2","article-title":"Important Roles for Angiotensin III and IV in the Brain Renin-Angiotensin System","volume":"25","author":"Wright","year":"1997","journal-title":"Brain Res. Rev."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"7775","DOI":"10.1073\/pnas.0402312101","article-title":"Brain Renin-Angiotensin System Blockade by Systemically Active Aminopeptidase A Inhibitors: A Potential Treatment of Salt-Dependent Hypertension","volume":"101","author":"Fassot","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"e70008","DOI":"10.1002\/cbf.70008","article-title":"Aminopeptidase A: A Novel Therapeutic Target for Hypertension Management","volume":"42","author":"Sharma","year":"2024","journal-title":"Cell Biochem. Funct."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1177\/1470320312474856","article-title":"Cardiovascular Effects of Angiotensin A: A Novel Peptide of the Renin\u2013Angiotensin System","volume":"15","author":"Coutinho","year":"2014","journal-title":"J. Renin. Angiotensin Aldosterone Syst."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"956","DOI":"10.1161\/HYPERTENSIONAHA.110.161836","article-title":"Pressor and Renal Hemodynamic Effects of the Novel Angiotensin A Peptide Are Angiotensin II Type 1A Receptor Dependent","volume":"57","author":"Yang","year":"2011","journal-title":"Hypertension"},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Flor, J., Silveira, A.T., Martins, I.A., Otero, L.B., Silva, F.M., Vizuete, A.F.K., Wink, M.R., and Rigatto, K. (2025). Biological Actions of Alamandine: A Scoping Review. Biomedicines, 13.","DOI":"10.20944\/preprints202506.1985.v1"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1007\/s10557-020-07114-6","article-title":"Research Progress on Pulmonary Arterial Hypertension and the Role of the Angiotensin Converting Enzyme 2-Angiotensin-(1\u20137)-Mas Axis in Pulmonary Arterial Hypertension","volume":"36","author":"Zhang","year":"2022","journal-title":"Cardiovasc. Drugs Ther."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"4428","DOI":"10.1111\/bph.15619","article-title":"Asthma: Role of the Angiotensin-(1-7)\/Mas (MAS1) Pathway in Pathophysiology and Therapy","volume":"178","author":"Santos","year":"2021","journal-title":"Br. J. Pharmacol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"2586","DOI":"10.1038\/s41418-020-0522-3","article-title":"Angiotensin-(1\u20139) Prevents Cardiomyocyte Hypertrophy by Controlling Mitochondrial Dynamics via miR-129-3p\/PKIA Pathway","volume":"27","author":"Morales","year":"2020","journal-title":"Cell Death Differ."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1038\/s41569-019-0244-8","article-title":"Counter-Regulatory Renin\u2013Angiotensin System in Cardiovascular Disease","volume":"17","author":"Riquelme","year":"2020","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1038\/s41420-022-00822-y","article-title":"Alamandine Alleviates Hypertension and Renal Damage via Oxidative-Stress Attenuation in Dahl Rats","volume":"8","author":"Gong","year":"2022","journal-title":"Cell Death Discov."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"C606","DOI":"10.1152\/ajpcell.00399.2021","article-title":"An Overview of Alamadine\/MrgD Signaling and Its Role in Cardiomyocytes","volume":"324","author":"Jesus","year":"2023","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Soltani Hekmat, A., Chenari, A., Alipanah, H., and Javanmardi, K. (2021). Protective Effect of Alamandine on Doxorubicin-induced Nephrotoxicity in Rats. BMC Pharmacol. Toxicol., 22.","DOI":"10.1186\/s40360-021-00494-x"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"e12306","DOI":"10.1111\/1755-5922.12306","article-title":"Alamandine Reverses Hyperhomocysteinemia-induced Vascular Dysfunction via PKA -dependent Mechanisms","volume":"35","author":"Qaradakhi","year":"2017","journal-title":"Cardiovasc. Ther."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1253\/circj.CJ-12-1544","article-title":"Multiple Functions of Angiotensin-Converting Enzyme 2 and Its Relevance in Cardiovascular Diseases","volume":"77","author":"Kuba","year":"2013","journal-title":"Circ. J."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1161\/CIRCULATIONAHA.120.047049","article-title":"Angiotensin Converting Enzyme 2: A Double-Edged Sword","volume":"142","author":"Wang","year":"2020","journal-title":"Circulation"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1186\/s13054-020-03120-0","article-title":"Role of Angiotensin-Converting Enzyme 2 (ACE2) in COVID-19","volume":"24","author":"Ni","year":"2020","journal-title":"Crit. Care"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1291\/hypres.26.937","article-title":"Molecular Analysis of the Structure and Function of the Angiotensin II Type 1 Receptor","volume":"26","author":"Miura","year":"2003","journal-title":"Hypertens. Res."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"S95","DOI":"10.1046\/j.1523-1755.1998.06719.x","article-title":"Physiological and Pharmacological Implications of AT1 versus AT2 Receptors","volume":"54","author":"Chung","year":"1998","journal-title":"Kidney Int."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1051","DOI":"10.1124\/pharmrev.120.000281","article-title":"The Angiotensin AT2 Receptor: From a Binding Site to a Novel Therapeutic Target","volume":"74","author":"Steckelings","year":"2022","journal-title":"Pharmacol. Rev."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1161\/HYPERTENSIONAHA.122.20601","article-title":"Angiotensin II Type 1A Receptor Expressed in Smooth Muscle Cells Is Required for Hypertensive Vascular Remodeling in Mice Infused With Angiotensin II","volume":"80","author":"Okuno","year":"2023","journal-title":"Hypertension"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1097\/00005344-200401000-00003","article-title":"Different AT1 Receptor Subtypes at Pre- and Postjunctional Sites: AT1A versus AT1B Receptors","volume":"43","author":"Nap","year":"2004","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/S0031-6997(24)01458-3","article-title":"International Union of Pharmacology. XXIII. The Angiotensin II Receptors","volume":"52","author":"Catt","year":"2000","journal-title":"Pharmacol. Rev."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/0167-0115(95)00030-F","article-title":"Disulfide Bridges in Extracellular Domains of Angiotensin II Receptor Type IA","volume":"57","author":"Ohyama","year":"1995","journal-title":"Regul. Pept."},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Colin, M., Delaitre, C., Foulquier, S., and Dupuis, F. (2023). The AT1\/AT2 Receptor Equilibrium Is a Cornerstone of the Regulation of the Renin Angiotensin System beyond the Cardiovascular System. Molecules, 28.","DOI":"10.3390\/molecules28145481"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1126\/science.aay9813","article-title":"Angiotensin and Biased Analogs Induce Structurally Distinct Active Conformations within a GPCR","volume":"367","author":"Wingler","year":"2020","journal-title":"Science"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1126\/science.aaz0326","article-title":"Molecular Mechanism of Biased Signaling in a Prototypical G Protein\u2013Coupled Receptor","volume":"367","author":"Suomivuori","year":"2020","journal-title":"Science"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"9662","DOI":"10.1021\/bi000597v","article-title":"Photolabeling Identifies Position 172 of the Human AT1 Receptor as a Ligand Contact Point: Receptor-Bound Angiotensin II Adopts an Extended Structure","volume":"39","author":"Boucard","year":"2000","journal-title":"Biochemistry"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"R71","DOI":"10.1530\/JME-14-0125","article-title":"Structural Determinants for Binding, Activation, and Functional Selectivity of the Angiotensin AT1 Receptor","volume":"53","author":"Balakumar","year":"2014","journal-title":"J. Mol. Endocrinol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"4410","DOI":"10.1021\/jm0103155","article-title":"Angiotensin II vs Its Type I Antagonists: Conformational Requirements for Receptor Binding Assessed from NMR Spectroscopic and Receptor Docking Experiments","volume":"45","author":"Wilkes","year":"2002","journal-title":"J. Med. Chem."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"2284","DOI":"10.1074\/jbc.270.5.2284","article-title":"Tetrazole and Carboxylate Groups of Angiotensin Receptor Antagonists Bind to the Same Subsite by Different Mechanisms","volume":"270","author":"Noda","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"3002","DOI":"10.2174\/1381612811319170005","article-title":"Class- and Molecule-Specific Differential Effects of Angiotensin II Type 1 Receptor Blockers","volume":"19","author":"Imaizumi","year":"2013","journal-title":"Curr. Pharm. Des."},{"key":"ref_95","first-page":"1171","article-title":"Angiotensin II Receptors-Antagonists, Molecular Biology, and Signal Transduction","volume":"36","author":"Jagadeesh","year":"1998","journal-title":"Indian J. Exp. Biol."},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Miura, S., Kiya, Y., Hanzawa, H., Nakao, N., Fujino, M., Imaizumi, S., Matsuo, Y., Yanagisawa, H., Koike, H., and Komuro, I. (2012). Small Molecules with Similar Structures Exhibit Agonist, Neutral Antagonist or Inverse Agonist Activity toward Angiotensin II Type 1 Receptor. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0037974"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"8621","DOI":"10.1021\/bi9830516","article-title":"Role of N-Glycosylation in the Expression and Functional Properties of Human AT1 Receptor","volume":"38","author":"Leclerc","year":"1999","journal-title":"Biochemistry"},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Zhang, Z., Liu, C., Gong, J., Su, C., Liu, Z., Li, J., and Zhang, H. (2025). Distinct Phosphorylation Patterns of AT1R by Biased Ligands and GRK Subtypes. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26167988"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1038\/sj.bjp.0706725","article-title":"S -nitrosylation of Cysteine 289 of the AT1 Receptor Decreases Its Binding Affinity for Angiotensin II","volume":"148","author":"Leclerc","year":"2006","journal-title":"Br. J. Pharmacol."},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Hessler, G., and Baringhaus, K.-H. (2018). Artificial Intelligence in Drug Design. Molecules, 23.","DOI":"10.3390\/molecules23102520"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1021\/ci500747n","article-title":"Deep Neural Nets as a Method for Quantitative Structure\u2013Activity Relationships","volume":"55","author":"Ma","year":"2015","journal-title":"J. Chem. Inf. Model."},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Mayr, A., Klambauer, G., Unterthiner, T., and Hochreiter, S. (2016). DeepTox: Toxicity Prediction Using Deep Learning. Front. Environ. Sci., 3.","DOI":"10.3389\/fenvs.2015.00080"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1007\/s11427-018-9342-2","article-title":"Artificial Intelligence in Drug Design","volume":"61","author":"Zhong","year":"2018","journal-title":"Sci. China Life Sci."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"108810","DOI":"10.1016\/j.compbiomed.2024.108810","article-title":"Application of Artificial Intelligence in Drug Design: A Review","volume":"179","author":"Singh","year":"2024","journal-title":"Comput. Biol. Med."},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Chatzipieris, F.P., Mavromoustakou, K., Matsoukas, J.M., and Mavromoustakos, T. (2025). Unlocking Novel Therapeutic Potential of Angiotensin II Receptor Blockers. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26188819"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"26208","DOI":"10.1021\/acsomega.5c00134","article-title":"New Prospects in the Inhibition of Monoamine Oxidase-B (MAO-B) Utilizing Propargylamine Derivatives for the Treatment of Alzheimer\u2019s Disease: A Review","volume":"10","author":"Chatzipieris","year":"2025","journal-title":"ACS Omega"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1517\/13543784.6.5.489","article-title":"Angiotensin II Receptor Antagonists\u2014Antihypertensive Agents","volume":"6","author":"Burnier","year":"1997","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"4196","DOI":"10.1021\/acs.jmedchem.1c00123","article-title":"Selective Discovery of GPCR Ligands within DNA-Encoded Chemical Libraries Derived from Natural Products: A Case Study on Antagonists of Angiotensin II Type I Receptor","volume":"64","author":"Liang","year":"2021","journal-title":"J. Med. Chem."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"104042","DOI":"10.1016\/j.bioorg.2020.104042","article-title":"Design, Synthesis and Biological Evaluation of Novel Fluoro-Substituted Benzimidazole Derivatives with Anti-Hypertension Activities","volume":"101","author":"Wu","year":"2020","journal-title":"Bioorganic Chem."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"129349","DOI":"10.1016\/j.bmcl.2023.129349","article-title":"Design, Synthesis and Biological Evaluation of Novel Indole-3-Carboxylic Acid Derivatives with Antihypertensive Activity","volume":"90","author":"Danilenko","year":"2023","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1016\/S0149-2918(96)80061-0","article-title":"The Angiotensin II Type 1 Receptor Blocker Losartan in Clinical Practice: A Review","volume":"18","author":"Gavras","year":"1996","journal-title":"Clin. Ther."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1016\/j.ejmech.2012.12.044","article-title":"Rational Design, Efficient Syntheses and Biological Evaluation of N, N\u2032-Symmetrically Bis-Substituted Butylimidazole Analogs as a New Class of Potent Angiotensin II Receptor Blockers","volume":"62","author":"Agelis","year":"2013","journal-title":"Eur. J. Med. Chem."},{"key":"ref_113","doi-asserted-by":"crossref","unstructured":"Ridgway, H., Apostolopoulos, V., Moore, G.J., Gadanec, L.K., Zulli, A., Swiderski, J., Tsiodras, S., Kelaidonis, K., Chasapis, C.T., and Matsoukas, J.M. (2024). Computational Evidence for Bisartan Arginine Blockers as Next-Generation Pan-Antiviral Therapeutics Targeting SARS-CoV-2, Influenza, and Respiratory Syncytial Viruses. Viruses, 16.","DOI":"10.3390\/v16111776"},{"key":"ref_114","doi-asserted-by":"crossref","unstructured":"Moore, G.J., Ridgway, H., Kelaidonis, K., Chasapis, C.T., Ligielli, I., Mavromoustakos, T., Bojarska, J., and Matsoukas, J.M. (2022). Actions of Novel Angiotensin Receptor Blocking Drugs, Bisartans, Relevant for COVID-19 Therapy: Biased Agonism at Angiotensin Receptors and the Beneficial Effects of Neprilysin in the Renin Angiotensin System. Molecules, 27.","DOI":"10.3390\/molecules27154854"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"2091","DOI":"10.1016\/j.csbj.2022.04.010","article-title":"Discovery of a New Generation of Angiotensin Receptor Blocking Drugs: Receptor Mechanisms and in Silico Binding to Enzymes Relevant to SARS-CoV-2","volume":"20","author":"Ridgway","year":"2022","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1016\/j.ejmech.2012.07.040","article-title":"The Discovery of New Potent Non-Peptide Angiotensin II AT1 Receptor Blockers: A Concise Synthesis, Molecular Docking Studies and Biological Evaluation of N-Substituted 5-Butylimidazole Derivatives","volume":"55","author":"Agelis","year":"2012","journal-title":"Eur. J. Med. Chem."},{"key":"ref_117","doi-asserted-by":"crossref","unstructured":"Kelaidonis, K., Ligielli, I., Letsios, S., Vidali, V.P., Mavromoustakos, T., Vassilaki, N., Moore, G.J., Hoffmann, W., W\u0119grzyn, K., and Ridgway, H. (2023). Computational and Enzymatic Studies of Sartans in SARS-CoV-2 Spike RBD-ACE2 Binding: The Role of Tetrazole and Perspectives as Antihypertensive and COVID-19 Therapeutics. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24098454"},{"key":"ref_118","doi-asserted-by":"crossref","unstructured":"Ridgway, H., Ntallis, C., Chasapis, C.T., Kelaidonis, K., Matsoukas, M.-T., Plotas, P., Apostolopoulos, V., Moore, G., Tsiodras, S., and Paraskevis, D. (2023). Molecular Epidemiology of SARS-CoV-2: The Dominant Role of Arginine in Mutations and Infectivity. Viruses, 15.","DOI":"10.3390\/v15020309"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1007\/BF01116558","article-title":"Angiotensin as a Model for Hormone\u2014Receptor Interactions","volume":"5","author":"Moore","year":"1985","journal-title":"Biosci. Rep."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"5303","DOI":"10.1016\/S0021-9258(17)37688-3","article-title":"Role of the NH2-Terminal Domain of Angiotensin II (ANG II) and [Sar1]Angiotensin II on Conformation and Activity. NMR Evidence for Aromatic Ring Clustering and Peptide Backbone Folding Compared with [Des-1,2,3]Angiotensin II","volume":"269","author":"Matsoukas","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1021\/jm00383a015","article-title":"Synthesis and Biological Activities of Analogs of Angiotensins II and III Containing O-Methyltyrosine and D-Tryptophan","volume":"28","author":"Matsoukas","year":"1985","journal-title":"J. Med. Chem."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"1418","DOI":"10.1021\/jm00402a028","article-title":"Importance of the N-Terminal Domain of the Type II Angiotensin Antagonist Sarmesin for Receptor Blockade","volume":"31","author":"Matsoukas","year":"1988","journal-title":"J. Med. Chem."},{"key":"ref_123","doi-asserted-by":"crossref","unstructured":"Ridgway, H., Chasapis, C.T., Kelaidonis, K., Ligielli, I., Moore, G.J., Gadanec, L.K., Zulli, A., Apostolopoulos, V., Mavromoustakos, T., and Matsoukas, J.M. (2022). Understanding the Driving Forces That Trigger Mutations in SARS-CoV-2: Mutational Energetics and the Role of Arginine Blockers in COVID-19 Therapy. Viruses, 14.","DOI":"10.3390\/v14051029"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1080\/14728222.2024.2362675","article-title":"Novel Benzimidazole Angiotensin Receptor Blockers with Anti-SARS-CoV-2 Activity Equipotent to That of Nirmatrelvir: Computational and Enzymatic Studies","volume":"28","author":"Ridgway","year":"2024","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"1639","DOI":"10.1016\/S0968-0896(01)00059-1","article-title":"Synthesis and Study of a Cyclic Angiotensin II Antagonist Analogue Reveals the Role of \u03a0*\u2013\u03a0* Interactions in the C-Terminal Aromatic Residue for Agonist Activity and Its Structure Resemblance with AT1 Non-Peptide Antagonists","volume":"9","author":"Polevaya","year":"2001","journal-title":"Bioorganic Med. Chem."},{"key":"ref_126","doi-asserted-by":"crossref","unstructured":"Ridgway, H., Moore, G.J., Gadanec, L.K., and Matsoukas, J.M. (2025). Docking Simulations of G-Protein Coupled Receptors Uncover Crossover Binding Patterns of Diverse Ligands to Angiotensin, Alpha-Adrenergic and Opioid Receptors: Implications for Cardiovascular Disease and Addiction. Biomolecules, 15.","DOI":"10.3390\/biom15060855"},{"key":"ref_127","unstructured":"MacroModel, L.L.C. (2013). Version 10, Maestro Schr\u00f6dinger."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/16\/1\/20\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,26]],"date-time":"2025-12-26T05:12:31Z","timestamp":1766725951000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/16\/1\/20"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,22]]},"references-count":127,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["biom16010020"],"URL":"https:\/\/doi.org\/10.3390\/biom16010020","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,22]]}}}