Advances in Designing Drugs That Block the Angiotensin II Receptor for Better Blood Pressure Treatment (2020–2024) | Research

The takeaway

This review surveys four years of advances in designing angiotensin II type 1 receptor antagonists — including large peptides, small molecules, and sartan derivatives — using structural biology and computational chemistry.

Vast unexplored chemical space
Novel non-sartan AT1R antagonists showed very low IC50 values, demonstrating that structurally diverse compounds beyond current drug classes could yield more potent blood pressure medications

What the researchers found

The review identified three categories of AT1R antagonists investigated from 2020 to 2024: large peptide molecules, small non-peptide-like molecules, and sartan derivatives. Notably, some non-sartan compounds exhibited very low IC50 values (indicating high potency), demonstrating that there is substantial chemical space beyond current drug classes that could yield more effective antihypertensive medications.

Computational chemistry analysis revealed the key molecular interactions governing binding affinity at the AT1R active site, explaining why structurally diverse compounds show different potencies. The review also updated understanding of AT1R structure-function relationships based on recent cryo-EM and crystallographic data.

Why it matters

Hypertension affects over 1.2 billion people globally and is the leading modifiable risk factor for cardiovascular disease. While existing sartans (ARBs) are effective, many patients don't achieve adequate blood pressure control. Discovering new chemical classes of AT1R antagonists — particularly those with higher potency or different pharmacological profiles — could lead to better treatments for resistant hypertension and provide alternatives for patients who don't respond well to current options.

How the study worked

This is a comprehensive literature review covering 2020–2024 publications on AT1R structure, function, and inhibitor design. The authors supplemented the literature analysis with their own computational chemistry studies — molecular docking and binding energy calculations — to identify key interactions between diverse antagonist molecules and the AT1R binding site. In vitro and in vivo potency data from published studies were compared across compound classes.

What this study cannot tell us

This is a narrative review without systematic methodology or meta-analysis. The computational modeling is supplementary and reflects the authors' specific docking protocols. Many of the novel compounds reviewed are in early preclinical stages with no clinical data. The comparison across different studies with varying assay conditions limits direct potency comparisons.

How to read the evidence

This is a narrative review synthesizing preclinical and computational research from 2020–2024. It provides a useful overview of the field but does not present original clinical data or systematic evidence grading.

When this study was published

Published in 2025, this review covers the most recent four years (2020–2024) of AT1R antagonist research, making it a current snapshot of this drug design field.

The bigger picture

The RAAS (renin-angiotensin-aldosterone system) has been a central focus of cardiovascular drug development for decades, yielding ACE inhibitors, ARBs, and direct renin inhibitors. This review shows that even in this well-explored space, there remains significant opportunity for innovation — particularly through computational drug design and exploration of non-traditional chemical scaffolds. The integration of cryo-EM structural data with computational modeling represents the modern approach to peptide receptor pharmacology.

Questions still open

Can the novel non-sartan AT1R antagonists identified in this review advance to clinical trials for resistant hypertension?
Could peptide-based AT1R antagonists offer advantages over small-molecule sartans in terms of selectivity or tissue distribution?
How do the computational predictions of binding affinity correlate with actual clinical efficacy in human blood pressure studies?

Common questions

What are sartans and why might we need alternatives?

Sartans (also called ARBs, or angiotensin receptor blockers) like losartan and valsartan are widely used blood pressure drugs that work by blocking the AT1 receptor. While effective for many people, some patients don't achieve adequate control. This review highlights new compounds — including peptide-based and non-traditional molecules — that could be more potent or work differently than existing sartans.

How does computational chemistry help design better blood pressure drugs?

Computational chemistry uses computer simulations to model how drug molecules fit into the AT1 receptor's binding site. By calculating binding energies and identifying key molecular interactions, researchers can predict which chemical modifications will make a compound more potent — saving years of trial-and-error lab work in the drug design process.

Read the original research

Structural and Computational Insights into the Angiotensin II Type 1 Receptor: Advances in Antagonist Design and Implications for Hypertension Therapy (2020-2024).

Biomolecules, 16(1)

View on PubMed ↗Publisher’s paper ↗

Citation

Chatzipieris, Filippos Panteleimon; Petsas, Errikos; Lambrinidis, George; Matsoukas, John M; Mavromoustakos, Thomas. (2025). Structural and Computational Insights into the Angiotensin II Type 1 Receptor: Advances in Antagonist Design and Implications for Hypertension Therapy (2020-2024).. Biomolecules, 16(1). https://doi.org/10.3390/biom16010020