通过将配体拉过脂质膜快速估算血脑屏障通透性。,Journal of Chemical Information and Modeling

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通过将配体拉过脂质膜快速估算血脑屏障通透性。
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2020-05-29 , DOI: 10.1021/acs.jcim.9b00834
Nguyen Quoc Thai _{1,

2} , Panagiotis E Theodorakis ₃ , Mai Suan Li ₃

Affiliation

血脑屏障（BBB）是调节神经微环境稳态的物理屏障。对BBB渗透性的相对估计，这对药物设计很重要，可以通过logBB（血脑浓度比）和logPS（通透性-表面积积）实验地提供，而许多计算方法旨在确定关键与这些数量相关的特性。尽管当前现有的计算方法（例如，定量结构活性关系）在筛选各种可能通过BBB转移的化合物方面做出了重大贡献，但它们无法提供基本过程的物理解释，并且通常对计算有要求。这里，W _neq，是通过将化合物拉过膜而产生的。我们发现，对于一系列化合物以及不同的膜类型和拉动速度，W _neq的值与logBB和logPS显着相关，而与力场的选择无关。此外，我们的结果提供了对氢键，高能屏障以及在拉动过程中施加在配体上的作用力的见解。我们的方法在计算上易于实现且快速。因此，我们预期它可以提供一种可靠的预筛查工具，用于估算BBB对各种物质的相对渗透率。

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Fast Estimation of the Blood-Brain Barrier Permeability by Pulling a Ligand through a Lipid Membrane.

The blood–brain barrier (BBB) is a physical barrier that regulates the homeostasis of the neural microenvironment. A relative estimate of the BBB permeability, which is important for drug design, may be experimentally provided by the logBB (the blood–brain concentration ratio) and the logPS (permeability–surface-area product), while many computational methods aim to identify key properties that correlate well with these quantities. Although currently existing computational methods (e.g., quantitative structure activity relation) have made a significant contribution in screening various compounds that could potentially translocate through the BBB, they are unable to provide a physical explanation of the underlying processes and they can often be computationally demanding. Here, we use steered molecular dynamics simulation to estimate the BBB permeability of various compounds on the basis of simple lipid–membrane models by computing the nonequilibrium work, W_neq, produced by pulling the compounds through the membrane. We found that the values of W_neq correlate remarkably well with logBB and logPS for a range of compounds and different membrane types and pulling speeds, independently of the choice of force field. Moreover, our results provide insight into the role of hydrogen bonds, the energetic barriers, and the forces exerted on the ligands during their pulling. Our method is computationally easy to implement and fast. Therefore, we anticipate that it could provide a reliable prescreening tool for estimating the relative permeability of the BBB to various substances.

更新日期：2020-06-23

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