Conformational Effects on the Passive Membrane Permeability of Synthetic Macrocycles

Our recent study, paper published in the Journal of Medicinal Chemistry, marks a promising advancement in understanding how synthetic Macrocycles can be optimized for drug design. By studying how the 3D structure and flexibility of these molecules influence their ability to cross cell membranes, we have reported on valuable insights that can help make Macrocycles more effective in targeting challenging disease-related proteins.

The Challenge

Designing drugs that can efficiently pass through cell membranes is essential for oral therapies, yet it is particularly challenging for larger molecules like macrocycles. Traditional design methods often overlook the effects of a molecule’s 3D conformation on its permeability, limiting the development of macrocycles as viable drug candidates.

Our Approach

We analyzed the passive permeability of over 3,600 diverse synthetic macrocycles, using machine learning to develop predictive models based on both 2D and 3D molecular descriptors. This approach allowed us to identify the role specific structural features, such as the spatial distribution of hydrophobic and hydrophilic regions, play in enabling these molecules to permeate membranes effectively.

Key Insights

We analyzed the passive permeability of over 3,600 diverse synthetic macrocycles, using machine learning to develop predictive models based on both 2D and 3D molecular descriptors. This approach allowed us to identify how specific structural features, such as the spatial distribution of hydrophobic and hydrophilic regions, play a role in enabling these molecules to permeate membranes effectively.

1.Effective Predictive Models:
By using machine learning, we developed models with strong predictive accuracy, achieving Q² scores of 0.79 and 0.74 for neutral and positively charged macrocycles, respectively. These models help predict how well a molecule might permeate cell membranes, offering guidance early in the design process.

2.Role of Molecular Flexibility: 

Our findings highlight the potential benefits of “chameleonic” properties—conformational flexibility that allows molecules to adjust their shape and hide polar regions in a membrane-like environment. This adaptability appears to be beneficial for improving permeability.

3.Guidance for Future Design:
By identifying functional group modifications that enhance permeability, our study provides actionable insights for designing macrocycles that balance both membrane permeability and bioavailability.

Moving Forward

This research offers a practical step toward designing macrocycles with improved permeability, making them more viable as drug candidates for difficult targets. While more work remains, these findings bring us closer to creating new classes of drugs that could tackle complex and previously hard-to-target proteins.
Our team is pleased to contribute to the evolving field of macrocycle research, and we look forward to seeing how these insights support ongoing efforts in drug discovery.