Permeability at Scale: The Weighted Ensemble Method in Orion, was presented by David LeBard, PhD, Senior Scientific Software Developer at OpenEye, on Tuesday, May 5, 2020 at 1 pm EDT / 10am PDT (US).
The rate of passive diffusion of a small molecule across a biological membrane is an important metric in structure-based drug discovery and can potentially influence both ADME and toxicity in late-stage drug development. Experimental determination of passive permeability through model membranes is feasible, however it requires a molecule to first be synthesized so it cannot routinely be done in earlier stages of the development cycle. While efforts have been made to improve computational determination of membrane permeability, essentially all simulation-based methods exhibit slow convergence times and often show poor correlation across different families of small molecules. Here, we present an alternative method to calculate passive membrane permeability using a path sampling technique known as the Weighted Ensemble method. This permeability model has been implemented as a floe in Orion using the WESTPA toolkit, and preliminary results over a diverse set of molecules are promising. This webinar will discuss the background of the Weighted Ensemble method, how the permeability calculation is implemented in Orion, and will present results using this method from a set of short-chained alcohols and drug-like molecules.