UMR CNRS 6230, Chimie Et Interdisciplinarité: Synthèse, Analyse, Modélisation (CEISAM), UFR Sciences & Techniques, Université de Nantes, NANTES Cedex, France.
J Comput Aided Mol Des. 2012 Oct;26(10):1111-26. doi: 10.1007/s10822-012-9602-x. Epub 2012 Sep 13.
A quantitative analysis of the interaction sites of the anti-Alzheimer drug galanthamine with molecular probes (water and benzene molecules) representative of its surroundings in the binding site of acetylcholinesterase (AChE) has been realized through pairwise potentials calculations and quantum chemistry. This strategy allows a full and accurate exploration of the galanthamine potential energy surface of interaction. Significantly different results are obtained according to the distances of approaches between the various molecular fragments and the conformation of the galanthamine N-methyl substituent. The geometry of the most relevant complexes has then been fully optimized through MPWB1K/6-31 + G(d,p) calculations, final energies being recomputed at the LMP2/aug-cc-pVTZ(-f) level of theory. Unexpectedly, galanthamine is found to interact mainly from its hydrogen-bond donor groups. Among those, CH groups in the vicinity of the ammonium group are prominent. The trends obtained provide rationales to the predilection of the equatorial orientation of the galanthamine N-methyl substituent for binding to AChE. The analysis of the interaction energies pointed out the independence between the various interaction sites and the rigid character of galanthamine. The comparison between the cluster calculations and the crystallographic observations in galanthamine-AChE co-crystals allows the validation of the theoretical methodology. In particular, the positions of several water molecules appearing as strongly conserved in galanthamine-AChE co-crystals are predicted by the calculations. Moreover, the experimental position and orientation of lateral chains of functionally important aminoacid residues are in close agreement with the ones predicted theoretically. Our study provides relevant information for a rational drug design of galanthamine based AChE inhibitors.
通过成对势计算和量子化学方法，对阿尔茨海默病药物加兰他敏与分子探针（水和苯分子）在乙酰胆碱酯酶（AChE）结合部位的相互作用位点进行了定量分析。该策略允许充分准确地探索加兰他敏的相互作用势能表面。根据各种分子片段与加兰他敏 N-甲基取代基构象之间的接近距离，得到了显著不同的结果。然后，通过 MPWB1K/6-31+G(d,p)计算对最相关配合物的几何形状进行了完全优化，最终能量在 LMP2/aug-cc-pVTZ(-f)理论水平上重新计算。出乎意料的是，加兰他敏主要通过其氢键供体基团相互作用。其中，铵基团附近的 CH 基团尤为突出。所得到的趋势为加兰他敏 N-甲基取代基与 AChE 结合时的赤道取向偏好提供了合理的解释。相互作用能的分析指出了各个相互作用位点之间的独立性和加兰他敏的刚性特征。簇计算与加兰他敏-AChE 共晶晶体中的晶体观察结果的比较验证了理论方法的有效性。特别是，计算预测了在加兰他敏-AChE 共晶晶体中出现的几个水分子的位置，这些水分子被强烈保守。此外，功能重要氨基酸残基侧链的实验位置和取向与理论预测的位置非常吻合。我们的研究为基于加兰他敏的 AChE 抑制剂的合理药物设计提供了相关信息。
