Prediction of Passive Membrane Permeability by Semi‐Empirical Method Considering Viscous and Inertial Resistances and Different Rates of Conformational Change and Diffusion

Abstract

Membrane permeability is an important property of drugs in adsorption. Many prediction methods work well for small molecules, but the prediction of middle-molecule permeability is still difficult. In the present study, we modified a classical permeability model based on Fick's law to study passive membrane permeability. The model consisted of the distribution of solute from water to membrane and the diffusion of solute in each solvent. The diffusion coefficient is the inverse of the resistance, and we examined the inertial resistance in addition to the viscous resistance, the latter of which has been widely used in permeability prediction. Also, we examined three models changing the balance between the diffusion of solute in membrane and the conformational change of solute. The inertial resistance improved the prediction results in addition to the viscous resistance. The models worked well not only for small molecules but also for middle molecules, whose structures have more conformational freedom.

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

“…Unsurprisingly, the permeation of small molecules through the lipid bilayer was among the first membrane-related topics studied through MD simulation, e.g., in 2004, Bemporad et al [149] studied permeation of small organic molecules like benzene or ethanol, and in older studies, Marrink and Berendsen (1994) studied permeation of water [564]. A significant amount of work has been performed to predict the permeability of small molecules through lipid bilayers using various molecular modeling methods and theoretical tools [565][566][567][568][569][570][571][572][573][574]; this includes new computational methodologies, developed specifically for the study of membrane permeability [575][576][577]. A web server and database PerMM is dedicated to gathering experimental and computational data related to small molecule membrane partitioning and translocation [578].…”

Flexibility and Cell Permeability of Cyclic Ras-Inhibitor Peptides Revealed by the Coupled Nosé–Hoover Equation

“…The cyclic peptide should be compact, closed, and polar to enable its efficient attachment to the membrane surface as the initial stage of membrane penetration. , The dipole moment was found to increase from Cluster 1 to Clusters 2/3/3*, or with decreasing PC2 and compact-closed conformation. The increase of the dipole moment is due to the alignment of the side chains in the CPP-like motif, especially Arg5–Arg6–dNal7–Arg8, ,, and to their stabilization via the cation−π interactions, which were randomized in Cluster 1 but had similar directions in Clusters 2/3/3* (see representative structures of the clusters in Figure ).…”

“…The cyclic peptide should be compact, closed, and polar to enable its efficient attachment to the membrane surface as the initial stage of membrane penetration. 10,11 The dipole moment Descending order of the probability, p. b Thickness in unit of Å 2 . See Figure S3a and Section 2 for definition.…”

“…Passive diffusion is considered one of the most probable mechanisms for cell permeability in case of cyclic peptides . Desirable properties for the passive permeation include small molecular radius (facilitates diffusion), high lipophilicity (enhances affinity to the lipophilic membrane), and positive charge (ensures affinity toward the negatively charged membrane surface). , These properties are strongly dependent on the instant structure that varies largely in thermal fluctuation. , Hence, quantitative examination of the structural dynamics of the cyclic peptides and structural modulations in response to the change of the surrounding environment is essential to predict their cell permeability.…”

“…The simulations were carried out in both explicit water and DMSO, corresponding to the recent nuclear magnetic resonance (NMR) experiment . Since the cell permeability is related to the structural fluctuations in aqueous environment before the peptide entry into the membrane, our simulation analyses focused on the structural ensembles in water, while the simulated structures in DMSO, which has been used as a membrane mimetic, , were also briefly discussed for comparison. A significant change in the structural dynamics and statistically averaged physical quantities were demonstrated via the modification from 9A5 to 9A54, which directly correlated with the decreased cell permeability.…”