van der Wenden E M, Price S L, Apaya R P, IJzerman A P, Soudijn W
Leiden-Amsterdam Center for Drug Research, Division of Medicinal Chemistry, Gorlaeus Laboratories, The Netherlands.
J Comput Aided Mol Des. 1995 Feb;9(1):44-54. doi: 10.1007/BF00117277.
The electrostatic properties of adenosine-based agonists and xanthine-based antagonists for the adenosine A1 receptor were used to assess various proposals for their relative orientation in the unknown binding site. The electrostatic properties were calculated from distributed multipole representations of SCF wavefunctions. A range of methods of assessing the electrostatic similarity of the ligands were used in the comparison. One of the methods, comparing the sign of the potential around the two molecules, gave inconclusive results. The other approaches, however, provided a mutually complementary and consistent picture of the electrostatic similarity and dissimilarity of the molecules in the three proposed relative orientations. This was significantly different from the results obtained previously with MOPAC AM1 point charges. In the standard model overlay, where the aromatic nitrogen atoms of both agonists and antagonists are in the same position relative to the binding site, the electrostatic potentials are so dissimilar that binding to the same receptor site is highly unlikely. Overlaying the N6-region of adenosine with that near C8 of theophylline (the N6-C8 model) produces the greatest similarity in electrostatic properties for these ligands. However, N6-cyclopentyladenosine (CPA) and 1,3-dipropyl-8-cyclopentyl-xanthine (DPCPX) show greater electrostatic similarity when the aromatic rings are superimposed according to the flipped model, in which the xanthine ring is rotated around its horizontal axis. This difference is mainly attributed to the change in conformation of N6-substituted adenosines and could result in a different orientation for theophylline and DPCPX within the receptor binding site. However, it is more likely that DPCPX also binds according to the N6-C8 model, as this model gives the best steric overlay and would be favoured by the lipophilic forces, provided that the binding site residues could accommodate the different electrostatic properties in the N6/N7-region. Finally, we have shown that Distributed Multipole Analysis (DMA) offers a new, feasible tool for the medicinal chemist, because it provides the use of reliable electrostatic models to determine plausible relative binding orientations.
基于腺苷的激动剂和基于黄嘌呤的腺苷A1受体拮抗剂的静电性质被用于评估它们在未知结合位点中相对取向的各种提议。静电性质是根据SCF波函数的分布式多极表示计算得出的。在比较中使用了一系列评估配体静电相似性的方法。其中一种方法，比较两个分子周围电势的符号，得到了不确定的结果。然而，其他方法提供了关于分子在三种提议的相对取向中的静电相似性和差异的相互补充且一致的图景。这与之前使用MOPAC AM1点电荷获得的结果有显著不同。在标准模型叠加中，激动剂和拮抗剂的芳香氮原子相对于结合位点处于相同位置，静电势差异如此之大，以至于不太可能与相同的受体位点结合。将腺苷的N6区域与茶碱的C8附近区域叠加（N6-C8模型），这些配体在静电性质上产生最大的相似性。然而，当根据翻转模型叠加芳香环时，N6-环戊基腺苷（CPA）和1,3-二丙基-8-环戊基黄嘌呤（DPCPX）显示出更大的静电相似性，在翻转模型中黄嘌呤环绕其水平轴旋转。这种差异主要归因于N6-取代腺苷构象的变化，并且可能导致茶碱和DPCPX在受体结合位点内的不同取向。然而，更有可能的是DPCPX也根据N6-C8模型结合，因为该模型提供了最佳的空间叠加，并且如果结合位点残基能够容纳N6/N7区域中不同的静电性质，将受到亲脂力的青睐。最后，我们已经表明，分布式多极分析（DMA）为药物化学家提供了一种新的可行工具，因为它提供了使用可靠的静电模型来确定合理的相对结合取向。
