Dataset Information

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

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.

SUBMITTER: Kamenik AS

PROVIDER: S-EPMC7388155 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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

Kamenik Anna S AS Kraml Johannes J Hofer Florian F Waibl Franz F Quoika Patrick K PK Kahler Ursula U Schauperl Michael M Liedl Klaus R KR

Journal of chemical information and modeling 20200629 7

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 s ...[more]

PMID: 32551643

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Project description:Accurate yet efficient computational models of solvent environment are central for most calculations that rely on atomistic modeling, such as prediction of protein-ligand binding affinities. In this study, we evaluate the accuracy of a recently developed generalized Born implicit solvent model, GBNSR6 (Aguilar et al. J. Chem. Theory Comput. 2010, 6, 3613-3639), in estimating the electrostatic solvation free energies (ΔG(pol)) and binding free energies (ΔΔG(pol)) for small protein-ligand complexes. We also compare estimates based on three different explicit solvent models (TIP3P, TIP4PEw, and OPC). The two main findings are as follows. First, the deviation (RMSD = 7.04 kcal/mol) of GBNSR6 binding affinities from commonly used TIP3P reference values is comparable to the deviations between explicit models themselves, e.g. TIP4PEw vs TIP3P (RMSD = 5.30 kcal/mol). A simple uniform adjustment of the atomic radii by a single scaling factor reduces the RMS deviation of GBNSR6 from TIP3P to within the above "error margin" - differences between ΔΔG(pol) estimated by different common explicit solvent models. The simple radii scaling virtually eliminates the systematic deviation (ΔΔG(pol)) between GBNSR6 and two out of the three explicit water models and significantly reduces the deviation from the third explicit model. Second, the differences between electrostatic binding energy estimates from different explicit models is disturbingly large; for example, the deviation between TIP4PEw and TIP3P estimates of ΔΔG(pol) values can be up to ∼50% or ∼9 kcal/mol, which is significantly larger than the "chemical accuracy" goal of ∼1 kcal/mol. The absolute ΔG(pol) calculated with different explicit models could differ by tens of kcal/mol. These discrepancies point to unacceptably high sensitivity of binding affinity estimates to the choice of common explicit water models. The absence of a clear "gold standard" among these models strengthens the case for the use of accurate implicit solvation models for binding energetics, which may be orders of magnitude faster.

Dataset Information

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

Publications

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

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