Abstract
ABSTRACTAssessing the permeation rate of drug-like molecules across a lipid membrane is of paramount importance for pharmaceutical applications. While the Meyer-Overton rule relates the permeability coefficient to a few thermodynamic properties, its accuracy is limited by the homogeneity assumption. In this work, we extract an analogous relation for the permeation of a small solute through a lipid bilayer. This is obtained by systematically screening a subset of chemical space by means of high-throughput coarse-grained simulations, and relying on the accurate inhomogeneous solubility-diffusion model (ISDM). We connect the permeability coefficient of a compound to two molecular descriptors: partitioning free-energy and acid dissociation constant. In the ISDM the permeability is a functional of the potential of mean force. We discuss how – and when – combining together these profiles for a large variety of compounds can result in a smooth dependence of the permeability on the molecular descriptors. We focus on acidic molecules: for weak acids, the permeability largely depends on the main free-energy differences of the problem, which directly link to our molecular descriptors. For strong acids, the multivalued nature of the permeability requires to introduce a third variable, characterising the amphiphilicity of the small molecule.Abbreviations: CG: coarse-grained; HTCG: high-throughput coarse-grained; PMF: potential of mean force; ISDM: inhomogeneous solubility-diffusion model; DOPC: 1; 2-Dioleoyl-sn-glycero-3-phosphocholine
Highlights
The strong binding affinity of a small drug-like candidate to the specific intracellular target, alone, does not guarantee its efficacy
While the Meyer-Overton rule links the permeability of a compound across a lipid bilayer to the partitioning coefficient, its validity is limited by the homogeneity assumption
In the inhomogeneous solubilitydiffusion model (ISDM), the permeability coefficient is a functional of the potential of mean force (PMF)
Summary
The strong binding affinity of a small drug-like candidate to the specific intracellular target, alone, does not guarantee its efficacy. Understanding the transport mechanism of small molecules through lipid bilayers is of fundamental importance for pharmaceutical applications. Transmembrane transport processes are usually divided in two classes [2]: (i) carrier-mediated processes, and (ii) passive permeation, i.e. diffusion of the permeant driven only by its concentration gradient and thermal fluctuations. Both classes can contribute to the total transport of a solute, passive permeation is believed to play a dominant role in the case of small drug-like molecules [3].
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