A Method to Predict Blood-Brain Barrier Permeability of Drug-Like Compounds Using Molecular Dynamics Simulations

Abstract

The blood-brain barrier (BBB) is formed by specialized tight junctions between endothelial cells that line brain capillaries to create a highly selective barrier between the brain and the rest of the body. A major problem to overcome in drug design is the ability of the compound in question to cross the BBB. Neuroactive drugs are required to cross the BBB to function. Conversely, drugs that target other parts of the body ideally should not cross the BBB to avoid possible psychotropic side effects. Thus, the task of predicting the BBB permeability of new compounds is of great importance. Two gold-standard experimental measures of BBB permeability are logBB (the concentration of drug in the brain divided by concentration in the blood) and logPS (permeability surface-area product). Both methods are time-consuming and expensive, and although logPS is considered the more informative measure, it is lower throughput and more resource intensive. With continual increases in computer power and improvements in molecular simulations, in silico methods may provide viable alternatives. Computational predictions of these two parameters for a sample of 12 small molecule compounds were performed. The potential of mean force for each compound through a 1,2-dioleoyl-sn-glycero-3-phosphocholine bilayer is determined by molecular dynamics simulations. This system setup is often used as a simple BBB mimetic. Additionally, one-dimensional position-dependent diffusion coefficients are calculated from the molecular dynamics trajectories. The diffusion coefficient is combined with the free energy landscape to calculate the effective permeability (Peff) for each sample compound. The relative values of these permeabilities are compared to experimentally determined logBB and logPS values. Our computational predictions correlate remarkably well with both logBB (R(2) = 0.94) and logPS (R(2) = 0.90). Thus, we have demonstrated that this approach may have the potential to provide reliable, quantitatively predictive BBB permeability, using a relatively quick, inexpensive method.

In silico screening of drug-membrane thermodynamics reveals linear relations between bulk partitioning and the potential of mean force

“…Indeed, as a first test of the accuracy of a coarse-grained potential of mean force in reproducing the permeability of a compound, we computed the log P value of mannitol in a DOPC membrane at T = 323K, and compared it to reference atomistic results. 6 We assumed a uniform diffusion coefficient D(z) = D ≈ 0.85 · 10 −6 cm 2 /s, by performing a graphical extrapolation of the average value reported in Ref. 6.…”

“…Although assuming a constant diffusion coefficient represents an approximation, D(z) was shown to be essentially uniform inside the membrane environment and for different compounds. 6 …”

Physiology of ionophore transport of potassium and sodium ions across cell membranes: valinomycin and 18-crown-6 ether

“…There is also evidence that the interactions between the zwitterionic head group of phosphatidylcholine moiety of cell membranes and polar molecular species can assist transport of these species across cell membranes by altering the membrane dipole potential. [Carpenter 2014] The formation of a {valinomycin-PC} complex at the interface surface of the membrane (most probably via an amide carbonyl oxygen) which then allows insertion of K + would affect the alter the dipole potential V D (possibly by ca. 45 mV [Warshaviak 2011]) facilitating permeation of the {valinomycin-K + } after it desorbs from the membrane surface or is displaced from the surface by another free valinomycin molecule.…”

In silicoADME/T modelling for rational drug design

“…However, this parameter merely reflects the total drug concentration in the brain rather than providing any insight into the free drug concentration. Log PS is a more appropriate index because it eliminates the effect of PPB or non-specific brain binding and provides a direct measure of BBB apparent permeability (Carpenter et al 2014). However, in vivo models are often low-throughput, expensive, and labour-intensive, and there are no in vitro models that can mimic all of the properties of the in vivo BBB.…”

“…As a result, the model demonstrated good predictive power for both internal and external validations. Recently, Carpenter et al (2014) predicted the log BB and log PS of 12 small molecules through a simple BBB mimic using MD and binding free energy calculations. After the MD simulations of each compound through a bilayer and free-energy calculation, the effective permeability combining the diffusion coefficient and free energy landscape was calculated, and the values correlated well with both log BB and log PS.…”