December 4, 2023 12:00 pm
December 4, 2023 1:15 pm
High-Throughput Technologies to Illuminate the Molecular Basis of Membrane Penetration within the Rule of 5 and Beyond
University of California, Irvine
How do molecules cross the cell membrane and what properties allow them to do so? Lipinski’s Rule of 5 generally defines physicochemical properties (molecular weight, lipophilicity) that correlate with good membrane permeability and oral bioavailability. Increasingly, drug discovery projects involve so called “undruggable” protein targets, which generally benefit from chemical space beyond the Lipinski's rule of 5 (bRo5), but these molecules suffer compromised cellular permeability and bioavailability due to unclear structure-permeation relationships. I have developed high-throughput permeation measurement technology – which could elucidate such relationships – as demonstrated through the discovery of unexpected relationships between stereochemistry and membrane permeation. My talk will describe this discovery and its potential implications for drug discovery and the origins of life. I will also discuss our ongoing efforts to explore and define the properties that confer membrane permeability within the Rule of 5 and beyond.