Computational model for predicting chemical substituent effects on passive drug permeability across parallel artificial membranes.
Computational model for predicting chemical substituent effects on passive drug permeability across parallel artificial membranes.
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DOI：
10.1021/mp800035h
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发表时间：
2008-09
影响因子：
4.9
通讯作者：
Mackerell AD Jr
中科院分区：
文献类型：
--
作者：
Acharya C;Seo PR;Polli JE;Mackerell AD Jr
药物渗透性通常是药物作用的限制步骤，需要对候选药物进行化学优化来改善这一特性。这种优化通常在同类系列的背景下进行，其中取代基被改变以优化目标性质。出于这一需要，本工作考察了化学取代基对三种同类化合物：苯甲酸、吡啶和喹啉的平行人工膜(PAMPA)的被动渗透性(LogP Pass)的影响。PAMPA显示，吡啶和喹啉具有高渗透性，化学取代基通常可以降低渗透性。相反，苯甲酸表现出较差的渗透性，而化学取代基典型地增加了渗透性。为了量化这些与物理性质相关的影响，建立了基于计算的分子描述符来解释和预测这些类化合物的渗透性的模型。苯甲酸系列在电离状态下的模型表明，溶剂可达表面积、空穴分散和在正己烷和水中的溶剂化自由能控制渗透性。然而，当酸性基团被作为中性基团处理时，水中的溶剂化自由能、部分极性表面积、正己烷和水之间的溶剂化自由能差以及这些项对于中性吡啶−喹啉系列也是重要的。考虑到苯甲酸系列的渗透性比吡啶和喹啉低约两个数量级，并且在苯甲酸的酸性基团的pKa中移动大约两个pH单位将允许分子的中性物种在实验条件下(pH=6.5)占主导地位，这些结果表明与苯甲酸系列的渗透相关的额外能垒与需要质子化酸性基团有关，从而形成中性物种，然后可能穿过膜的疏水区域。
Drug permeability is often a limiting step in drug action, requiring chemical optimization of a drug candidate to improve this property. Such optimization is typically performed in the context of a congeneric series, where substituents are varied to optimize the target property. Motivated by this need the present work examines the influence of chemical substituents on passive permeability (log P pass) across parallel artificial membranes (PAMPA) undertaken for three congeneric series of compounds; benzoic acids, pyridines and quinolines. PAMPA showed pyridine and quinoline to have high permeability and chemical substituents to typically reduce the permeability. On the contrary, benzoic acid showed poor permeability and chemical substituents typically increased the permeability. To quantitate these effects with respect to physical properties, models were built to explain and predict the permeability of these classes of compounds based on computed molecular descriptors. Models for the benzoic acid series in the ionized state indicated the solvent accessible surface area, cavity dispersion and the free energy of solvation in hexane as well as in water to dominate permeability. However, when the acid group is treated as neutral, the free energy of solvation in water, the fraction polar surface area, the polar surface area and difference in the free energy of solvation between hexane and water were important; these terms, among others, were also important for the neutral pyridine−quinoline series. Considering that the permeability of the benzoic acid series is about 2 orders of magnitude lower than the pyridines and quinolines and that a shift of approximately two pH units in the pK a of the acid group of benzoic acid will allow for the neutral species of the molecule to dominate under experimental conditions (pH = 6.5), these results suggest that the additional energy barrier associated with permeation of the benzoic acid series is associated with the need to protonate the acidic group, thereby forming the neutral species which may then cross the hydrophobic region of the membrane.
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影响因子：
2.9
作者：
Panigrahi, Sunil K.;Desiraju, Gautam R.
通讯作者：
Desiraju, Gautam R.
影响因子：
5.6
作者：
LEE, B;RICHARDS, FM
通讯作者：
RICHARDS, FM
影响因子：
64.8
作者：
CHOTHIA, C
通讯作者：
CHOTHIA, C
DOI：
10.1016/s0006-291x(02)02996-0
发表时间：
2003-01-31
影响因子：
3.1
作者：
Pillai, AD;Rathod, PD;Sudarsanam, V
通讯作者：
Sudarsanam, V
影响因子：
3
作者：
BROOKS, BR;BRUCCOLERI, RE;KARPLUS, M
通讯作者：
KARPLUS, M