Malaisree Maturos, Rungrotmongkol Thanyada, Decha Panita, Intharathep Pathumwadee, Aruksakunwong Ornjira, Hannongbua Supot
Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand.
Proteins. 2008 Jun;71(4):1908-18. doi: 10.1002/prot.21897.
To provide detailed information and insight into the drug-target interaction, structure, solvation, and dynamic and thermodynamic properties, the three known-neuraminidase inhibitors-oseltamivir (OTV), zanamivir (ZNV), and peramivir (PRV)-embedded in the catalytic site of neuraminidase (NA) subtype N1 were studied using molecular dynamics simulations. In terms of ligand conformation, there were major differences in the structures of the guanidinium and the bulky groups. The atoms of the guanidinium group of PRV were observed to form many more hydrogen bonds with the surrounded residues and were much less solvated by water molecules, in comparison with the other two inhibitors. Consequently, D151 lying on the 150-loop (residues 147-152) of group-1 neuraminidase (N1, N4, N5, and N8) was considerably shifted to form direct hydrogen bonds with the --OH group of the PRV, which was located rather far from the 150-loop. For the bulky group, direct hydrogen bonds were detected only between the hydrophilic side chain of ZNV and residues R224, E276, and E277 of N1 with rather weak binding, 20-70% occupation. This is not the case for OTV and PRV, in which flexibility and steric effects due to the hydrophobic side chain lead to the rearrangement of the surrounded residues, that is, the negatively charged side chain of E276 was shifted and rotated to form hydrogen bonds with the positively charged moiety of R224. Taking into account all the ligand-enzyme interaction data, the gas phase MM interaction energy of -282.2 kcal/mol as well as the binding free energy (DeltaG(binding)) of -227.4 kcal/mol for the PRV-N1 are significantly lower than those of the other inhibitors. The ordering of DeltaG(binding) of PRV < ZNV < OTV agrees well with the ordering of experimental IC(50) value.
为了提供关于药物 - 靶点相互作用、结构、溶剂化以及动力学和热力学性质的详细信息和深入见解，使用分子动力学模拟研究了嵌入神经氨酸酶（NA）亚型N1催化位点的三种已知神经氨酸酶抑制剂——奥司他韦（OTV）、扎那米韦（ZNV）和帕拉米韦（PRV）。在配体构象方面，胍基和庞大基团的结构存在主要差异。与其他两种抑制剂相比，观察到PRV胍基的原子与周围残基形成更多的氢键，并且被水分子溶剂化的程度更低。因此，位于1组神经氨酸酶（N1、N4、N5和N8）的150 - 环（残基147 - 152）上的D151显著移动，与位于离150 - 环相当远位置的PRV的 - OH基团形成直接氢键。对于庞大基团，仅在ZNV的亲水性侧链与N1的残基R224、E276和E277之间检测到直接氢键，结合较弱，占有率为20 - 70%。OTV和PRV并非如此，其中疏水侧链导致的柔韧性和空间效应导致周围残基重排，即E276带负电荷的侧链移动并旋转以与R224带正电荷的部分形成氢键。考虑到所有配体 - 酶相互作用数据，PRV - N1的气相MM相互作用能为 - 282.2 kcal/mol以及结合自由能（ΔG(binding)）为 - 227.4 kcal/mol，显著低于其他抑制剂。PRV < ZNV < OTV的ΔG(binding)排序与实验IC(50)值的排序非常吻合。
