Entropy and Polarity Control the Partition and Transportation of Drug-like Molecules in Biological Membrane

Abstract

Partition and transportation of drug in the plasma membrane of a mammalian cell are the prerequisite for its function on target protein. Therefore, comprehensive understanding of the physicochemical properties and mechanism behind these complex phenomena is crucial in pharmaceutical research. By using the state-of-art molecular simulations with polarization effect implicitly or explicitly included, we studied the permeation behavior of 2-aminoethoxydiphenyl borate (2-APB), a broad-spectrum modulator for a number of membrane proteins. We showed that the protonation state and therefore the polarity of the drug is critical for its partition, and that the drug is likely to switch between different protonation states along its permeation pathway. By changing the degrees of freedom, protonation further affects the thermodynamic of the permeation pathway of 2-APB, leading to different entropic contributions. A survey on 54 analog structures with similar backbone to 2-APB showed that delicate balance between entropy and polarity plays an important role in drugs’ potency.

Dynamic Protonation Dramatically Affects the Membrane Permeability of Drug-like Molecules

“…Yet using nonpolarizable force fields should not impair the major findings of this work, that is, dynamic protonation should be considered when investigating facile membrane permeation of ionizable molecules, which is also supported by a study including the polarization effects. 96…”

Gating and regulation of the calcium release‐activated calcium channel: Recent progress from experiments and molecular modeling

“…Therefore, it is summarized as the "twist-to-open" mechanism. [35] The electronic structure [103] and its dynamic behavior during membrane permeation [106] of 2-APB, the modulator of CRAC channel, have also been studied. Quantum mechanics calculations show the reversible interaction of Lewis pair between boron and nitrogen atoms enables this molecule to adopt different oligomeric states with different sizes.…”

“…MD simulations show a significant drop of pKa to ~4.0 upon membrane internalization, which was attributed to the incompatibility between the charged amine group and the hydrophobic core of membrane, indicating the possible deprotonation process during its permeations along the membrane bilayer. [ 106 ] Seemingly, the complex functionality of 2‐APB is associated with its ability to switch among isomeric forms, suited to different binding sites in the SOC channels with distinct binding affinities.…”

“…[ 103 ] Free energy calculations further disclosed the possibility of changing the protonation state of 2‐APB along its permeation pathway, as the p K a is 9.6 in bulk water, [ 104 ] and is calculated to drop to ~4 at the center of the membrane. [ 106 ] Therefore, the diversity in structure and the charge state of 2‐APB seems to account for its profound effect on regulation the CRAC channel.…”

Hydration Structure and Dynamics of the Favipiravir Antiviral Drug: A Molecular Modelling Approach

“…Since the predictive capability of molecular simulation techniques in computational pharmaceutics 17 , either by molecular dynamics or Monte Carlo, strongly relies on the quality of the potential model to describe the intermolecular interactions of the systems, several physicochemical parameters need to be carefully taken into account when developing these models. Particularly in the case of the prediction of transport properties of drugs, either in solution or in biological membranes, a crucial factor which strongly affects the diffusivity of the drug molecules is their polarity 18 . High level quantum mechanical calculations can be very helpful in estimating the polarity of drug molecules.…”