ArticleJournal of chemical information and modeling2020
Macrocycle Cell Permeability Measured by Solvation Free Energies in Polar and Apolar Environments.
Article in Journal of chemical information and modeling, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed.
- Quantifying Small-Molecule Association with Lipid Membranes: Methods, Models, and Limitations.Membranes · 2026Review
- Quantifying Spatially Resolved Hydration Thermodynamics Using Grid Inhomogeneous Solvation Theory [Article v1.0].Living journal of computational molecular science · 2025Article
- Improving the Accuracy of Permeability Data to Gain Predictive Power: Assessing Sources of Variability in Assays Using Cell Monolayers.Membranes · 2024Review
- Gaussian accelerated molecular dynamics simulations facilitate prediction of the permeability of cyclic peptides.PloS one · 2024Article
- Addressing Challenges of Macrocyclic Conformational Sampling in Polar and Apolar Solvents: Lessons for Chameleonicity.Journal of chemical information and modeling · 2023Article
- Cell-permeable chameleonic peptides: Exploiting conformational dynamics in de novo cyclic peptide design.Current opinion in structural biology · 2023Review
- Controlling the Evolution of Selective Vancomycin Resistance through Successful Ophthalmic Eye-Drop Preparation of Vancomycin-Loaded Nanoliposomes Using the Active-Loading Method.Pharmaceutics · 2023Article
- Computer aided drug design in the development of proteolysis targeting chimeras.Computational and structural biotechnology journal · 2023Review
- Enhanced sampling without borders: on global biasing functions and how to reweight them.Physical chemistry chemical physics : PCCP · 2022Review
- Cell Permeability of Isomeric Macrocycles: Predictions and NMR Studies.ACS medicinal chemistry letters · 2021Article
- Benchmark of Generic Shapes for Macrocycles.Journal of chemical information and modeling · 2020Article
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8 authors.
Funding
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.
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