Ring Size as an Independent Variable in Cyclooligomeric Depsipeptide Antiarrhythmic Activity

Area of Science:

• Medicinal Chemistry
• Chemical Biology
• Pharmacology

Background:

• Hit-to-lead studies traditionally optimize molecular interactions and 3D space.
• Leveraging ring size as an independent variable is challenging due to limited symmetry in most drug hits.
• The discovery of ent-verticilide's inhibition of cardiac ryanodine receptors presented a unique opportunity.

Purpose of the Study:

• To investigate the impact of ring size as an independent variable in drug optimization.
• To explore whether conformational changes alone, driven by ring size, can significantly influence binding potency.

Main Methods:

• Utilized the cyclic oligomeric depsipeptide ent-verticilide as a model compound.
• Focused on modifying the ring size of ent-verticilide while keeping other structural features constant.
• Assessed the inhibitory potency against mammalian cardiac ryanodine receptor calcium release channels.

Main Results:

• Demonstrated that ring size can be a critical independent variable in drug design.
• Showed that ent-verticilide inhibits cardiac ryanodine receptors with submicromolar potency.
• Confirmed that modest conformational alterations, solely through ring size modification, can profoundly impact compound potency.

Conclusions:

• Ring size is a viable and powerful independent variable for optimizing drug candidates.
• Conformational flexibility, influenced by ring size, plays a crucial role in achieving potent target engagement.
• This study provides a new strategy for medicinal chemistry optimization, particularly for cyclic compounds.