A least-squares-fitting procedure for an efficient preclinical ranking of passive transport across the blood–brain barrier endothelium

IF 3 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Computer-Aided Molecular Design Pub Date : 2023-08-12 DOI:10.1007/s10822-023-00525-1

Christian Jorgensen, Evan P. Troendle, Jakob P. Ulmschneider, Peter C. Searson, Martin B. Ulmschneider

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Abstract

The treatment of various disorders of the central nervous system (CNS) is often impeded by the limited brain exposure of drugs, which is regulated by the human blood–brain barrier (BBB). The screening of lead compounds for CNS penetration is challenging due to the biochemical complexity of the BBB, while experimental determination of permeability is not feasible for all types of compounds. Here we present a novel method for rapid preclinical screening of libraries of compounds by utilizing advancements in computing hardware, with its foundation in transition-based counting of the flux. This method has been experimentally validated for in vitro permeabilities and provides atomic-level insights into transport mechanisms. Our approach only requires a single high-temperature simulation to rank a compound relative to a library, with a typical simulation time converging within 24 to 72 h. The method offers unbiased thermodynamic and kinetic information to interpret the passive transport of small-molecule drugs across the BBB.

Graphical abstract

Abstract Image

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通过血脑屏障内皮被动转运的有效临床前排序的最小二乘拟合程序

各种中枢神经系统(CNS)疾病的治疗常常受到药物脑暴露有限的阻碍，这是由人血脑屏障(BBB)调节的。由于血脑屏障的生化复杂性，先导化合物的筛选具有挑战性，而通透性的实验测定并非适用于所有类型的化合物。在这里，我们提出了一种新的方法，用于快速临床前筛选化合物库，利用先进的计算硬件，其基础是基于过渡的通量计数。该方法已通过实验验证了体外渗透性，并提供了原子水平的转运机制的见解。我们的方法只需要一次高温模拟就可以对化合物进行相对于文库的排序，典型的模拟时间集中在24到72小时之间。该方法提供了无偏的热力学和动力学信息，可以解释小分子药物在血脑屏障上的被动转运。图形抽象

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来源期刊

Journal of Computer-Aided Molecular Design 生物-计算机：跨学科应用

CiteScore

8.00

自引率

8.60%

发文量

审稿时长

3 months

期刊介绍： The Journal of Computer-Aided Molecular Design provides a form for disseminating information on both the theory and the application of computer-based methods in the analysis and design of molecules. The scope of the journal encompasses papers which report new and original research and applications in the following areas: - theoretical chemistry; - computational chemistry; - computer and molecular graphics; - molecular modeling; - protein engineering; - drug design; - expert systems; - general structure-property relationships; - molecular dynamics; - chemical database development and usage.