MemCross: Accelerated Weight Histogram method to assess membrane permeability.

Area of Science:

• Computational chemistry
• Pharmacokinetics
• Drug discovery

Background:

• Passive permeation across biological membranes is key to drug pharmacokinetics.
• Accurate prediction of membrane permeation coefficients aids drug discovery by guiding lead selection.
• Current molecular dynamics simulations for permeation coefficients are computationally intensive.

Purpose of the Study:

• To develop and benchmark a novel, computationally affordable method for predicting membrane permeation coefficients.
• To address the challenge of conformational sampling for bulky, drug-like molecules in permeation studies.
• To establish a structure-activity relationship for xenobiotic permeation.

Main Methods:

• Application of the Accelerated Weight Histogram (AWH) method in all-atom membrane models, termed MemCross.
• Calculation of potential of mean force (PMF) profiles for drug-like xenobiotics.
• Modeling of subdiffusion and analysis of molecular orientations and interactions during permeation.

Main Results:

• The MemCross protocol provides affordable estimation of PMF profiles for drug-like xenobiotics.
• MemCross enables continuous exploration of permeation pathways and computation of fractional diffusivity.
• A coherent structure-activity relationship was established for a series of 12 xenobiotics.

Conclusions:

• MemCross offers a versatile and computationally efficient alternative to existing enhanced sampling methods for predicting membrane permeation.
• The method provides detailed insights into molecular behavior during permeation at atomic resolution.
• MemCross facilitates accurate prediction of drug bioavailability and supports rational drug design.