Macrocycle Cell Permeability Measured by Solvation Free Energies in Polar and Apolar Environments.

Anna S. Kamenik,Johannes Kraml,Ursula Kahler,Patrick K. Quoika,Klaus R. Liedl,Franz Waibl,Florian Hofer,Michael Schauperl

doi:10.1021/acs.jcim.0c00280

Anna S. Kamenik, Johannes Kraml + Show 6 more

Open Access

https://doi.org/10.1021/acs.jcim.0c00280

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Abstract

The relation of surface polarity and conformational preferences is decisive for cell permeability and thus bioavailability of macrocyclic drugs. Here, we employ grid inhomogeneous solvation theory (GIST) to calculate solvation free energies for a series of six macrocycles in water and chloroform as a measure of passive membrane permeability. We perform accelerated molecular dynamics simulations to capture a diverse structural ensemble in water and chloroform, allowing for a direct profiling of solvent-dependent conformational preferences. Subsequent GIST calculations facilitate a quantitative measure of solvent preference in the form of a transfer free energy, calculated from the ensemble-averaged solvation free energies in water and chloroform. Hence, the proposed method considers how the conformational diversity of macrocycles in polar and apolar solvents translates into transfer free energies. Following this strategy, we find a striking correlation of 0.92 between experimentally determined cell permeabilities and calculated transfer free energies. For the studied model systems, we find that the transfer free energy exceeds the purely water-based solvation free energies as a reliable estimate of cell permeability and that conformational sampling is imperative for a physically meaningful model. We thus recommend this purely physics-based approach as a computational tool to assess cell permeabilities of macrocyclic drug candidates.

Highlights

Macrocycles are a potent new class of molecules for drug discovery.[1,2] Approximately 75% of disease relevant proteins still cannot be targeted, neither with small molecules nor with biopharmaceuticals.[3]
We have previously shown the reliability of accelerated MD (aMD) simulations in characterizing the structural ensemble and thermodynamic quantities of macrocycles consistent with experiments.[31]
We show the ensemble distributions of both descriptors for the most permeable macrocycle in our series, 1f, compared to the least permeable compound 1e. For both systems, the number of intramolecular hydrogen bonds (IMHBs) is higher in chloroform, while the polar surface area shifts toward smaller values in the apolar environment

Summary

Introduction

Macrocycles are a potent new class of molecules for drug discovery.[1,2] Approximately 75% of disease relevant proteins still cannot be targeted, neither with small molecules nor with biopharmaceuticals.[3] A major portion of these yet undruggable targets are intracellular protein−protein interfaces (PPIs), including several notorious cancer-associated targets.[4] Biologics, such as antibodies, are the prime class of pharmaceuticals to target extracellular PPIs with uncontested specificities and affinities.[5,6] with a few exceptions, they are generally not able to cross through the cell membrane.[7] Smallmolecule drugs, on the other hand, are extremely well-studied, and clear models and guidelines to achieve oral bioavailability and membrane permeability are well-established.[8] they mostly require deep apolar binding pockets to achieve the desired affinities and physiological effects, which are lacking in typical PPIs with extensive flat surface areas.[3] Macrocycles bridge these two medication strategies in terms of physicochemical and pharmacological features.[9−12]

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