ASSESSING THE INTESTINAL PERMEABILITY OF SMALL MOLECULE DRUGS

Abstract

A protocol that accurately assesses the intestinal permeability of small molecule compounds plays an essential role in decreasing the cost and time in inventing a new drug. This manuscript presents a novel computational method to study the passive permeation of small molecule drugs based on the inhomogeneous solubility-diffusion model. The multidimensional free energy surface of the drug transiting through a lipid bilayer is computed with transition-tempered metadynamics that accurately captures the mechanisms of passive permeation. The permeability is computed by following the diffusion motion of the drug molecules along the minimal free energy path found on the multidimensional free energy surface. This computational method is assessed by studying the permeability of five small molecule drugs (ketoprofen, naproxen, metoprolol, propranolol, and salicylic acid). The results demonstrate a remarkable agreement between the computed permeabilities and those measured with the intestinal assay. The \textit{in silico} method reported in this manuscript also reproduces the permeability measured from the intestinal assay (\textit{in vivo}) better than the cell-based assays (e.g., PAMPA and Caco-2) do. In addition, the multidimensional free energy surface reveals the interplay between the structure of the small molecule and its permeability, shedding light on strategies of drug optimization. This new model was developed based on the inhomogeneous-solubility diffusion model. Our current model, although exceptional at predicting permeabilities, differs from the original theory derivation of the inhomogeneous-solubility diffusion model. This brings attention, through the study of ten small molecule drugs, that our new model and the original model need to be updated. The permeability shown by these ten small molecule drugs will touch on the issues of minimizing error in transition-tempered metadynamics simulations, and the importance of anchoring different points at zero when calculating permeability with the inhomogeneous-solubility diffusion model.