Fast calculation of molecular polar surface area as a sum of fragment-based contributions and its application to the prediction of drug transport properties
Fast calculation of molecular polar surface area as a sum of fragment-based contributions and its application to the prediction of drug transport properties
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DOI：
10.1021/jm000942e
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发表时间：
2000-10-05
影响因子：
7.3
通讯作者：
Selzer, P
中科院分区：
文献类型：
--
作者：
Ertl, P;Rohde, B;Selzer, P
分子极性表面积（PSA），即属于极性原子的表面，是一种描述符，被证明与通过膜的被动分子转运良好相关，因此可以预测药物的运输特性。然而，由于有必要产生合理的3D分子几何形状和表面本身的计算，因此PSA的计算很耗时。基于极地碎片的表面贡献的总结，这里介绍了一种新的PSA计算方法。该方法称为拓扑PSA（TPSA），提供了与3D PSA实际上相同的结果（3D PSA和基于片段的TPSA之间的相关系数的34 810分子来自世界药物指数为0.99），而计算速度为2-3个数量级。因此，新方法可以用于快速筛选具有数百万个分子的虚拟库。本文介绍了新方法，并根据已发表的吸收数据集（包括肠吸收，CACO-2单层渗透率和血脑屏障渗透）来显示验证研究的结果。
Molecular polar surface area (PSA), i.e., surface belonging to polar atoms, is a descriptor that was shown to correlate well with passive-molecular transport through membranes and, therefore, allows prediction of transport properties of drugs. The calculation of PSA, however, is rather time-consuming because of the necessity to generate a reasonable 3D molecular geometry and the calculation of the surface itself. A new approach for the calculation of the PSA is presented here, based on the summation of tabulated surface contributions of polar fragments. The method, termed topological PSA (TPSA), provides results which are practically identical with the 3D PSA (the correlation coefficient between 3D PSA and fragment-based TPSA for 34 810 molecules from the World Drug Index is 0.99), while the computation speed is 2-3 orders of magnitude faster. The new methodology may, therefore, be used for fast bioavailability screening of virtual libraries having millions of molecules. This article describes the new methodology and shows the results of validation studies based on sets of published absorption data, including intestinal absorption, Caco-2 monolayer penetration, and blood-brain barrier penetration.