Gresh Nohad
Laboratoire de Pharmacochimie Moléculaire et Cellulaire, FRE 2718 CNRS, U2648 INSERM, IFR Biomédicale, Université René-Descartes, Paris, France.
Curr Pharm Des. 2006;12(17):2121-58. doi: 10.2174/138161206777585256.
A correct representation of intermolecular interaction energies is necessary for reliable drug-receptor docking studies. While ab initio quantum chemistry with extended basis sets is the most accurate tool for that purpose, its use is precluded for very large molecular complexes. This constitutes the incentive for the development of accurate molecular mechanics potentials, in which the first-order electrostatic, and the second-order polarization energy contributions, are of essential importance. In this paper, we review the most important steps in the development of anisotropic, polarizable molecular mechanics (APMM) procedures. Among these, we illustrate validation tests of the ab initio-grounded, polarizable molecular mechanics potential, SIBFA (Sum of Interactions Between Fragments Ab initio computed). These are done by comparisons with parallel quantum-chemical (QC) results on representative multiply hydrogen-bonded complexes and polycoordinated complexes of one, or of two, divalent metal cations. For both kinds of complexes, the need to reproduce the non-additivity of the QC interaction energies is emphasized. One difficulty arises upon handling flexible molecules, due to the need to account simultaneously and consistently for the onset of inter- and intra-molecular polarization and charge-transfer effects. A new approach in the context of SIBFA was recently developed towards this aim, and tested in two cases of conformation-dependent cation-ligand interaction energies. The first relates to the complexes formed between the mecapto-carboxamide anion, an essential building-block of several Zn-metalloenzyme inhibitors, and Zn(II). The second relates to the complexes of the tetra-anionic pyrophosphate anion, a key building-block of ATP and GTP, with one or two divalent Zn(II) cations used as a probe. In the domain of applications, two recent studies are then presented. The first is the docking of the captopril drug to the active site of the binuclear Zn(II)- beta-lactamase enzyme. The second is the complex of a non-hydrolyzable analog of ATP with the active site of a binuclear Mg(II)-dependent kinase. An extension to an open-shell cation, Cu(II), is finally presented. The encouraging results presented in this review show that APMM procedures could be used in large-scale studies of ligand and drug-receptor interactions.
对于可靠的药物 - 受体对接研究而言，分子间相互作用能的正确表示是必要的。虽然使用扩展基组的从头算量子化学是实现此目的最精确工具，但对于非常大的分子复合物而言，其应用受到限制。这构成了开发精确分子力学势的动力，其中一阶静电和二阶极化能贡献至关重要。在本文中，我们回顾了各向异性、可极化分子力学（APMM）程序开发中的最重要步骤。其中，我们展示了基于从头算的可极化分子力学势SIBFA（片段间从头算计算相互作用之和）的验证测试。这些测试通过与具有代表性的多重氢键复合物以及一价或二价金属阳离子的多配位复合物的平行量子化学（QC）结果进行比较来完成。对于这两类复合物，都强调了重现QC相互作用能非加和性的必要性。在处理柔性分子时会出现一个难题，因为需要同时且一致地考虑分子间和分子内极化以及电荷转移效应的发生。最近在SIBFA背景下针对此目的开发了一种新方法，并在两个与构象相关的阳离子 - 配体相互作用能案例中进行了测试。第一个案例涉及巯基甲酰胺阴离子（几种锌金属酶抑制剂的基本组成部分）与Zn(II)形成的复合物。第二个案例涉及四阴离子焦磷酸根阴离子（ATP和GTP的关键组成部分）与用作探针的一个或两个二价Zn(II)阳离子形成的复合物。在应用领域，随后展示了两项近期研究。第一项是卡托普利药物与双核Zn(II)-β-内酰胺酶活性位点的对接。第二项是ATP的不可水解类似物与双核Mg(II)依赖性激酶活性位点形成的复合物。最后展示了对开壳阳离子Cu(II)的扩展。本综述中给出的令人鼓舞的结果表明，APMM程序可用于配体与药物 - 受体相互作用的大规模研究。
