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Article summary:
1. The challenge of finding selective ligands that stimulate a target receptor without stimulating off-target receptors associated with toxicity or undesirable side effects is addressed in this article.
2. The article focuses on the structural basis of efficacy-driven selectivity, which is different from affinity-driven selectivity and can provide a much broader therapeutic window.
3. Using computational and experimental approaches, the authors studied the ligand xanomeline to determine the molecular mechanism of its efficacy-driven selectivity at muscarinic acetylcholine receptors (mAChRs).
Article analysis:
The article “Structural basis of efficacy-driven ligand selectivity at GPCRs” by Nature Chemical Biology provides an interesting insight into the challenge of finding selective ligands that stimulate a target receptor without stimulating off-target receptors associated with toxicity or undesirable side effects. The article focuses on the structural basis of efficacy-driven selectivity, which is different from affinity-driven selectivity and can provide a much broader therapeutic window.
The authors use computational and experimental approaches to study the ligand xanomeline to determine the molecular mechanism of its efficacy-driven selectivity at muscarinic acetylcholine receptors (mAChRs). They find that xanomeline has nearly identical binding affinity for all five mAChR subtypes but significantly higher efficacy at M4 than M2, M3 and M5 mAChRs. They also observe that xanomeline binds differently in active vs inactive states between M2 and M4 mAChRs due to a sequence difference in extracellular loop 2 (ECL2).
The article is generally well written and provides an interesting insight into the topic. It presents evidence for its claims in a clear manner, using both computational and experimental approaches to support its findings. The authors also discuss potential implications for other GPCRs, although they acknowledge that further research is needed to understand how mechanisms of efficacy-driven selectivity differ across ligands and receptors.
In terms of trustworthiness and reliability, there are no obvious biases or one-sided reporting in this article; it presents both sides equally and does not appear to be promotional in nature. All claims are supported by evidence provided by either simulations or experiments, although some counterarguments may have been unexplored or missing points of consideration may have been overlooked. Additionally, possible risks associated with using such drugs are noted throughout the article, providing