Dholakia Dhwani, Goyal Sukriti, Jamal Salma, Singh Aditi, Das Asmita, Grover Abhinav
Department of Biotechnology, Delhi Technological University, New Delhi, 110042, India.
Department of Bioscience and Biotechnology, Banasthali University, Tonk, Rajasthan, 304022, India.
BMC Bioinformatics. 2016 Dec 22;17(Suppl 19):512. doi: 10.1186/s12859-016-1374-1.
Influenza virus spreads infection by two main surface glycoproteins, namely hemagglutinin (HA) and neuraminidase (NA). NA cleaves the sialic acid receptors eventually releasing newly formed virus particles which then invade new cells. Inhibition of NA could limit the replication of virus to one round which is insufficient to cause the disease.
An experimentally reported series of acylguanidine zanamivir derivatives was used to develop GQSAR model targeting NA in different strains of influenza virus, H1N1 and H3N2. A combinatorial library was developed and their inhibitory activities were predicted using the GQSAR model.
The top leads were analyzed by docking which revealed the binding modes of these inhibitors in the active site of NA (150-loop). The top compound (AMA) was selected for carrying out molecular dynamics simulations for 15 ns which provided insights into the time dependent dynamics of the designed leads. AMA possessed a docking score of -8.26 Kcal/mol with H1N1 strain and -7.00 Kcal/mol with H3N2 strain. Ligand-bound complexes of both H1N1 and H3N2 were observed to be stable for 11 ns and 7 ns respectively. ADME descriptors were also calculated to study the pharmacokinetic properties of AMA which revealed its drug-like properties.
流感病毒通过两种主要的表面糖蛋白传播感染，即血凝素（HA）和神经氨酸酶（NA）。NA切割唾液酸受体，最终释放新形成的病毒颗粒，这些颗粒随后侵入新的细胞。抑制NA可将病毒复制限制在一轮，这不足以引发疾病。
利用一系列实验报道的酰基胍扎那米韦衍生物开发了针对甲型流感病毒H1N1和H3N2不同毒株中NA的GQSAR模型。构建了一个组合文库，并使用GQSAR模型预测了它们的抑制活性。
通过对接分析了先导化合物，揭示了这些抑制剂在NA（150环）活性位点的结合模式。选择了最佳化合物（AMA）进行15纳秒的分子动力学模拟，这为所设计先导化合物的时间依赖性动力学提供了见解。AMA与H1N1毒株的对接分数为-8.26千卡/摩尔，与H3N2毒株的对接分数为-7.00千卡/摩尔。观察到H1N1和H3N2的配体结合复合物分别在11纳秒和7纳秒内保持稳定。还计算了AMA的ADME描述符以研究其药代动力学性质，结果显示其具有类药性质。
