THE EFFECT OF PHYSICAL ORGANIC PROPERTIES ON HYDROPHOBIC FIELDS
THE EFFECT OF PHYSICAL ORGANIC PROPERTIES ON HYDROPHOBIC FIELDS
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DOI：
10.1007/bf00124348
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发表时间：
1994-02-01
影响因子：
3.5
通讯作者：
KELLOGG, GE
中科院分区：
文献类型：
--
作者：
ABRAHAM, DJ;KELLOGG, GE
小分子和大分子的物理有机结构属性，如键数、分支和多个极性片段之间的接近程度，对测量的疏水性(LogP)有很大影响。这些结构特性被编码在作为结构依赖因子计算logP的Rekker和LEO方法中。无论原子基元集合的大小如何，仅使用原子基元预测logP的方法可能会错过一系列相关化合物中的微妙结构细节。HINT(分子间和分子内非共价相互作用)模型计算了基于原子的疏水常数，但在计算中使用了所有LEO类型的因子，而不是一大组原子基元。讨论了HINT的两种类型的应用：评估抑制物(A74704)与HIV-1蛋白酶的结合，其中表明对蛋白质中质子化状态(即Asp25 Asp125)的建模可以强烈影响感知的底物结合；使用HINT计算CoMFA的第三个(水路)场可以为分子设计产生统计增强和预测的模型。
Physical organic structural properties of small molecules and macromolecules such as bond count, branching and proximity between multiple polar fragments contribute significantly to measured hydrophobicity (log P). These structural properties are encoded in the Rekker and Leo methods of calculating log P as structural-dependent factors. Regardless of the size of the atom primitive set, methods predicting log P with only atom primitives can miss subtle structural detail within series of related compounds. The HINT (Hydropathic INTeractions) model for inter- and intramolecular noncovalent interactions calculates atom-based hydrophobic constants, but uses all Leo-type factors in the calculation rather than a large set of atom primitives. Two types of applications of HINT are discussed: evaluation of the binding of an inhibitor (A74704) to HIV-1 protease, where it is shown that modeling of the protonation state (i.e., Asp25 Asp125) in the protein can strongly influence perceived substrate binding; and the use of HINT to calculate a third (hydropathic) field for CoMFA can yield a statistically enhanced and predictive model for molecular design.