Soave Raffaella, Barzaghi Mario, Destro Riccardo
CNR-ISTM, Istituto di Scienze e Tecnologie Molecolari, Via Golgi 19, 20133 Milano, Italy.
Chemistry. 2007;13(24):6942-56. doi: 10.1002/chem.200601516.
A combined experimental and theoretical charge density study of an angiotensin II receptor antagonist (1) is presented focusing on electrostatic properties such as atomic charges, molecular electric moments up to the fourth rank and energies of the intermolecular interactions, to gain an insight into the physical nature of the drug-receptor interaction. Electrostatic properties were derived from both the experimental electron density (multipole refinement of X-ray data collected at T=17 K) and the ab initio wavefunction (single molecule and fully periodic calculations at the DFT level). The relevance of SO and SN intramolecular interactions on the activity of 1 is highlighted by using both the crystal and gas-phase geometries and their electrostatic nature is documented by means of QTAIM atomic charges. The derived electrostatic properties are consistent with a nearly spherical electron density distribution, characterised by an intermingling of electropositive and -negative zones rather than by a unique electrophilic region opposed to a nucleophilic area. This makes the first molecular moment scarcely significant and ill-determined, whereas the second moment is large, significant and highly reliable. A comparison between experimental and theoretical components of the third electric moment shows a few discrepancies, whereas the agreement for the fourth electric moment is excellent. The most favourable intermolecular bond is show to be an NHN hydrogen bond with an energy of about 50 kJ mol(-1). Key pharmacophoric features responsible for attractive electrostatic interactions include CHX hydrogen bonds. It is shown that methyl and methylene groups, known to be essential for the biological activity of the drug, provide a significant energetic contribution to the total binding energy. Dispersive interactions are important at the thiophene and at both the phenyl fragments. The experimental estimates of the electrostatic contribution to the intermolecular interaction energies of six molecular pairs, obtained by a new model proposed by Spackman, predict the correct relative electrostatic energies with no exceptions.
本文介绍了对一种血管紧张素II受体拮抗剂（1）进行的实验与理论电荷密度联合研究，重点关注静电性质，如原子电荷、直至四阶的分子电矩以及分子间相互作用能，以深入了解药物 - 受体相互作用的物理本质。静电性质既来自实验电子密度（在T = 17 K收集的X射线数据的多极精修），也来自从头算波函数（DFT水平的单分子和全周期计算）。通过使用晶体和气相几何结构突出了SO和SN分子内相互作用对1活性的相关性，并借助QTAIM原子电荷记录了它们的静电性质。推导得到的静电性质与近乎球形的电子密度分布一致，其特征是正电区和负电区相互交织，而非由与亲核区域相对的独特亲电区域构成。这使得一阶分子矩几乎不显著且难以确定，而二阶分子矩较大、显著且高度可靠。三阶电矩的实验和理论分量之间存在一些差异，而四阶电矩的一致性非常好。最有利的分子间键是能量约为50 kJ mol⁻¹的NHN氢键。负责有吸引力的静电相互作用的关键药效团特征包括CHX氢键。结果表明，已知对药物生物活性至关重要的甲基和亚甲基对总结合能有显著的能量贡献。色散相互作用在噻吩以及两个苯基片段处都很重要。通过Spackman提出的新模型获得的六个分子对分子间相互作用能的静电贡献的实验估计，无一例外地预测了正确的相对静电能。
