Assessing the Intestinal Permeability of Small Molecule Drugs via Diffusion Motion on a Multidimensional Free Energy Surface

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 in silico method reported in this manuscript also reproduces the permeability measured from the intestinal assay (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.

Predictions from First-Principles of Membrane Permeability to Small Molecules: How Useful Are They in Practice?

“…The paradigmatic example of water partitioning across a 1-palmitoyl-2-oleoyl- sn -phosphatidylcholine (POPC) bilayer provides a cogent illustration of fortuitous cancellation of errors, the TIP3P model of water overestimating both the differential solvation free energy between the aqueous and the hydrophobic media, and the diffusivity, yet supplying an estimate of P m of (141 ± 2) × 10 –4 cm/s, in very good agreement with the experimental value of (130 ± 4) × 10 –4 cm/s . Still, with nearly a decade of hindsight, and of membrane-permeability estimates from first-principles, using μs-long biased MD simulations for a variety of permeants, ,,− ,,,,− it is a fair assessment that current academic force fields are capable of supplying, in the best-case scenario, quantities within 1 order of magnitude from the consensus target experimental measurements. In general, however, discrepancies as large as two to 3 orders of magnitude are not uncommon, underscoring the necessity of more sophisticated potential energy functionseven though rigorous discrimination between the different sources of errors burdening the membrane-permeability estimates has remained elusive.…”

“…Nothing could be further from the truth. Attempts have been made to address the incompleteness of the model, coupling for instance the translation of the substrate along z to its reorientation as it partitions from one monolayer to the other, either through an explicit rotational degree of freedom, , or by means of two euclidean distances. , On the other hand, it is far from clear what the slow degrees of freedom are, and it is even less so how to account for them in the determination of free-energy change that underlies the translocation of the permeant.…”

Calculation of the permeability coefficients of small molecules through lipid bilayers by free-energy reaction network analysis following the explicit treatment of the internal conformation of the solute

“…Although the in vitro permeability of artificial membranes, such as PAMPA, predicts membrane permeability, it also generally exhibits a good correlation with cell permeability but with a lower value than the in vivo (natural membranes, biomembranes) results. 69 Thus, our results include specifically high membrane permeability for NAFA, indicating that our calculation underestimated the activation barrier of NAFA in the PMFs of the center of the lipid bilayer probably because of the quality of the force fields.…”

Physical Chemistry of Chloroquine Permeation through the Cell Membrane with Atomistic Detail

“…The center of the membrane is set to have z = 0. This CV has been used also in previous drug permeation studies: − Gaussians with 1.2 kJ mol –1 initial height and 0.5 Å sigma values were deposited every 2 ps, similarly to refs and . The bias factor for CQ + (25) is larger than that for CQ 0 (20), because a higher free energy barrier of the charged species is expected.…”

“…For the past decade, a variety of state-of-the-art enhanced sampling methods have successfully described the structure, dynamics and energetics of small molecule permeation. − Here we use well-tempered metadynamics (WTMetaD), an exact method to calculate the free energies of a process as a function of appropriate collective variables, , to describe the process. Our calculations are carried out for the two species CQ 0 and CQ + , in model membranes with different compositions or in the presence of a transmembrane potential.…”