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Estimating the Permeability of Molecules using Weighted Ensemble

Estimating the Permeability of Molecules using Weighted Ensemble

Join us for the miniWebinar "Estimating the Passive Membrane Permeability of Drug-Like Molecules using the Weighted Ensemble Enhanced Sampling Approach" presented by She Zhang, PhD, Scientific Developer at OpenEye, Cadence Molecular Sciences, on Thursday, September 22, 2022. 

Webinar Summary 

Passive permeability of a drug-like molecule is a critical assay early in a drug discovery campaign that informs a medicinal chemist how well a compound can traverse biological membranes, such as gastrointestinal epithelial or restrictive organ barriers, so it can perform a specific therapeutic function.

Typically, the membrane permeability of drug-like molecules is measured experimentally using either an artificial or natural membrane, or computationally by quantitative structure-permeability relationship (QSPR) models or solving the Smoluchowski equation, where free energy and diffusion profiles along the membrane normal are taken as input from large-scale molecular dynamics simulations.

While all these methods provide estimates of permeation coefficients, however, the challenge that remains is the development of a method, experimental or computational, which can both determine the permeation rate and provide mechanistic insights into the transport process to help with the rational design for any given molecule.

In the OpenEye Permeability Floes, we employ a highly parallelizable weighted ensemble (WE) path sampling strategy, empowered by cloud computing techniques, to generate unbiased permeation pathways and permeability coefficients for a set of drug-like molecules across a neat 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine (POPC) membrane bilayer.

Our WE-based floe predicts permeability coefficients that compare well to experimental values from an MDCK-LE cell line and PAMPA assays for a set of drug-like amines of varying size, shape, and flexibility. The WE method also yields a series of continuous permeation pathways weighted and ranked by their associated probabilities. Taken together, the ensemble of reactive permeation pathways, along with the estimate of the permeability coefficient, provides a clearer picture of the microscopic underpinnings of small molecule membrane permeation. 


Webinar Agenda

The presentation details are: 

  • Introduction to Permeability: Definition, Previous Models, and Our Kinetic Model
  • The Weighted Ensemble Enhanced Sampling Strategy and How it can be applied to Permeability 
  • Features of the OpenEye Permeability Floes 
  • Interpreting Permeability Results 
  • Future Perspectives & Conclusions 

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