Recent advances on molecular dynamics-based techniques to address drug membrane permeability with atomistic detail

Abstract

Several factors affect the passive membrane permeation of small molecules, including size, charge, pH, or the presence of specific chemical groups. Understanding these features is paramount to identifying or designing drug candidates with optimal ADMET properties and this can be achieved through experimental/knowledge-based methodologies or using computational approaches. Empirical methods often lack detailed information about the underlying molecular mechanism. In contrast, Molecular Dynamics-based approaches are a powerful strategy, providing an atomistic description of this process. This technique is continuously growing, featuring new related methodologies. In this work, the recent advances in this research area will be discussed.

Keywords: 0000; 1111; Constant-pH MD; Enhanced sampling; Lipid bilayer; Lipophilicity; Passive diffusion.

Graphical abstract

Fig. 1

Schematic representation of the PAMPA model, displaying the molecular movement of passive diffusion across a thin microfilter (synthetic membrane) separating two aqueous compartments.

Fig. 2

Representation of an Umbrella sampling (US) scheme presenting the respective windows, and applied to a POPC membrane model. The US windows references are illustrated by the horizontal lines shown across the system and, in this case, with the same spacing from each other. The arrow represents the distance to the membrane center which is usually used as the reference and k is the harmonic potential constant. The lipid head groups are shown as blue (cholines) and yellow (phosphates) spheres. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 3

Schematic representation of the molecular structure of a capped trialanine using three different atomistic levels. In the united-atom representation, all apolar hydrogen atoms are collapsed into their carbon atom. The GROMOS force field family is an example of this level of representation , . In the Martini force field family, the alanine residues are coarse-grained and represented as single beads , .