MemCross: Accelerated Weight Histogram method to assess membrane permeability

Passive permeation events across biological membranes are determining steps in the pharmacokinetics of xe-nobiotics. To reach an accurate and rapid prediction of membrane permeation coefficients of drugs is a complex challenge, which can efficiently support drug discovery. Such predictions are indeed highly valuable as they may guide the selection of potential leads with optimum bioavailabilities prior to synthesis. Theoretical models exist to predict these coefficients. Many of them are based on molecular dynamics (MD) simulations, which allow calculation of permeation coefficients through the evaluation of both the potential of mean force (PMF) and the diffusivity profiles. However, these simulations still require intensive computational efforts, and novel meth-odologies should be developed and benchmarked. Free energy perturbation (FEP) method was recently shown to estimate PMF with a significantly reduced computational cost compared to the adaptive biasing force method. This benchmarking was achieved with small molecules, namely short-chain alcohols. Here, we show that to estimate the PMF of bulkier, drug-like xenobiotics, conformational sampling is a critical issue. To reach a suf-ficient sampling with FEP calculations requires a relatively long time-scale, which can lower the benefits related to the computational gain. In the present work, the Accelerated Weight Histogram (AWH) method was employed for the first time in all-atom membrane models. The AWH-based protocol, named MemCross, appears affordable to estimate PMF profiles of a series of drug-like xenobiotics, compared to other enhanced sampling methods. The continuous exploration of the crossing pathway by MemCross also allows modeling subdiffusion by computing fractional diffusivity profiles. The method is also versatile as its input parameters are largely insensitive to the molecule properties. It also ensures a detailed description of the molecule orientations along the permeation pathway, picturing all intermolecular interactions at an atomic resolution. Here, MemCross was applied on a series of 12 xenobiotics, including four weak acids, and a coherent structure-activity relationship was established.

Automated summary

Passive permeation events across biological membranes play a crucial role in the pharmacokinetics of drugs. The accurate and rapid prediction of membrane permeation coefficients is important for drug discovery. The latest method, MemCross, based on the Accelerated Weight Histogram (AWH) protocol, is a cost-effective approach to estimate the potential of mean force (PMF) and diffusivity profiles of drug-like xenobiotics, providing a detailed description of molecule orientations and interactions. This method has been successfully applied to 12 xenobiotics and revealed a coherent structure-activity relationship.