基于神经氨酸酶结构的流感病毒抑制剂的计算机辅助药物设计

Computer aid drug design of novel inhibitors of influenza based on the crystal neuraminidase structure

目的:虚拟筛选更高活性的神经氨酸酶(NA)抑制剂,提高抵抗变异病毒的能力,为以后相关疾病治疗新药的设计提供科学依据。方法:利用Schrodinger Suite2009中的Glide模块对Leadnow数据库进行高通量虚拟筛选,对选出的结构用"Core Hop-ping"模块改造结构;利用Desmond2.4软件包进行分子动力学模拟研究,将NA的空载蛋白及靶点与筛选结果较好的配体小分子复合物共3个模型分别进行10 ns的分子动力学模拟。结果:高通量虚拟筛选得到一个五元环结构的化合物ZINC13219479,并以此为核心向150-cavity延伸,得到8个能很好进入的结构。建立了靶向这些位点的配体库,方便后续有关研究的进行。分子动力学结果表明模拟过程中各靶点与配体复合物体系稳定,结合位点正确。作为抑制剂,小分子配体与NA酶的150-cavity区域残基形成稳定的氢键作用,牢牢占据NA的催化位点。结论:通过计算机辅助设计得到的小分子与NA的结合能力理论上优于抑制剂达菲。在动力学模拟这些化合物后,更加确定了这些化合物的有效性,具有一定的科研价值。

Objective： To observe high activity agents of neuraminidase （NA） against H5N1 Swine influenza virus, and indicate the fur- ther research for discovery of novel class of inhibitors. Methods： The small molecule database of lead-now were high-throughput screened by Glide of Schrodinger Suite 2009, and the candidates were optimized by Core Hopping of Schrodinger Suite 2009; the 10ns MD simulation of NA protein with and without candidates were performed by software Desmond4.2. Results： ZINC13219479, a cyclopen- tane ring compound, was screened from the database, and 8 novel compounds were optimized by generating its side-chain towards 150- cavity. To guide the further research, the database of small molecules was established. Final results of MD simulations were exposed the stable combination of complex, and confirmed the binging site. The inhibitors, small molecules designed on silicon according to formed H-bond between the compounds and 150-cavity of enzyme NA, performed the strong interaction and negative effects to the receptor. Conclusion： One group of novel inhibitors is screened and optimized according to the combinational mode between osehamivir and NA obtained by Schrodinger Suite 2009, which is confirmed the combinational activities by molecular dynamics simulation by Desmond 2.4 as well.