Trogdon Gavin, Murray Jane S, Concha Monica C, Politzer Peter
Department of Chemistry, University of New Orleans, New Orleans, LA 70148, USA.
J Mol Model. 2007 Feb;13(2):313-8. doi: 10.1007/s00894-006-0145-8. Epub 2006 Sep 22.
General anesthetics apparently act through weak, noncovalent and reversible interactions with certain sites in appropriate brain proteins. As a means of gaining insight into the factors underlying anesthetic potency, we have analyzed the computed electrostatic potentials V (S)(r) on the surfaces of 20 molecules with activities that vary between zero and high. Our results are fully consistent with, and help to interpret, what has been observed experimentally. We find that an intermediate level of internal charge separation is required; this is measured by Pi, the average absolute deviation of V (S)(r), and the approximate window is 7 < Pi < 13 kcal mol(-1). This fits in well with the fact that anesthetics need to be lipid soluble, but also to have some degree of hydrophilicity. We further show that polyhalogenated alkanes and ethers, which include the most powerful known anesthetics, have strong positive potentials, V (S,max), associated with their hydrogens, chlorines and bromines (but not fluorines). These positive sites may impede the functioning of key brain proteins, for example by disrupting their normal hydrogen-bond patterns. It has indeed been recognized for some time that the most active polyhalogenated alkanes and ethers contain hydrogens usually in combination with chlorines and/or bromines.
全身麻醉药显然是通过与合适的脑蛋白中的某些位点进行弱的、非共价且可逆的相互作用来发挥作用的。作为深入了解麻醉效能潜在因素的一种方法，我们分析了20种活性在零到高之间变化的分子表面上计算出的静电势V(S)(r)。我们的结果与实验观察结果完全一致，并有助于对其进行解释。我们发现需要中等程度的内部电荷分离；这是通过Pi来衡量的，Pi是V(S)(r)的平均绝对偏差，大致范围是7 < Pi < 13千卡/摩尔(-1)。这与麻醉药需要脂溶性但也需要一定程度亲水性这一事实非常吻合。我们进一步表明，包括已知最强效麻醉药在内的多卤代烷烃和醚，其氢、氯和溴（但不是氟）具有很强的正电势V(S,max)。这些正电荷位点可能会阻碍关键脑蛋白的功能，例如通过破坏它们正常的氢键模式。事实上，人们早就认识到，最具活性的多卤代烷烃和醚通常含有与氯和/或溴结合的氢。
