Predictions from First-Principles of Membrane Permeability to Small Molecules: How Useful Are They in Practice?

Predicting from first-principles the rate of passivepermeationof small molecules across the biological membrane represents a promisingstrategy for screening lead compounds upstream in the drug-discoveryand development pipeline. One popular avenue for the estimation ofpermeation rates rests on computer simulations in conjunction withthe inhomogeneous solubility-diffusion model, which requiresthe determination of the free-energy change and position-dependentdiffusivity of the substrate along the translocation pathway throughthe lipid bilayer. In this Perspective, we will clarify the physicalmeaning of the membrane permeability inferred from such computer simulations,and how theoretical predictions actually relate to what is commonlymeasured experimentally. We will also examine why these calculationsremain both technically challenging and overly computationally expensive,which has hitherto precluded their routine use in nonacademic settings.We finally synopsize possible research directions to meet these challenges,increase the predictive power of physics-based rates of passive permeation,and, by ricochet, improve their practical usefulness.

Automated summary

Predicting the rate of passive permeation of small molecules across the biological membrane is a promising strategy for drug discovery. The estimation of permeation rates through computer simulations and the solubility-diffusion model requires determining the free-energy change and diffusivity of the substrate along the translocation pathway. This Perspective clarifies the physical meaning of membrane permeability from computer simulations and discusses the challenges and potential research directions to improve the predictive power and practical usefulness of physics-based rates of passive permeation.