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

Predicting from first-principles the rate of passive
permeation
of small molecules across the biological membrane represents a promising
strategy for screening lead compounds upstream in the drug-discovery
and development pipeline. One popular avenue for the estimation of
permeation rates rests on computer simulations in conjunction with
the inhomogeneous solubility–diffusion model, which requires
the determination of the free-energy change and position-dependent
diffusivity of the substrate along the translocation pathway through
the lipid bilayer. In this Perspective, we will clarify the physical
meaning of the membrane permeability inferred from such computer simulations,
and how theoretical predictions actually relate to what is commonly
measured experimentally. We will also examine why these calculations
remain 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.