Department of Bioinformatics, Computer Aided Drug Design and Molecular Modelling Lab, Alagappa University, Karaikudi- 630004, Tamil Nadu, India.
Curr Top Med Chem. 2018;18(18):1585-1602. doi: 10.2174/1568026618666181025100736.
Dengue fever, a major public health problem in the tropical and sub-tropical countries caused by the infection of Dengue virus transmitted by the anthropod vectors. The dengue virus infection is represented as the "Neglected Tropical Diseases" by the world health organization. The structural protein E binds to the receptor on the host cell surface during infection and the binding directs to the endocytic pathway. The conformational change of the envelope protein helps to infuse the viral lipid membrane and delivers the viral genome into the cytosol. No specific treatments are available till date and development of the vaccine for the DENV is challenging due to the immunization and longlasting protection against all four serotypes. Hence, identification of potent inhibitors would overlay the therapeutics against the mediated diseases.
Our study focuses on developing the novel potent inhibitors to inhibit the viral attachment and membrane fusion of the Dengue virus Envelope protein.
The crystal structure of Dengue Envelope protein has been retrieved from the protein data bank and optimized through Schrödinger. The structure-based virtual screening based on the cocrystallised ligand has been carried out with the small molecule libraries, and based on the docking score, interaction and energy value best complexes were selected. The selected complexes were further taken forward for the conformational stability analysis through Molecular dynamics simulation.
Around 55 molecules from the three databases were identified as potential binders to the envelope protein and the docking studies revealed that the top compounds possess strong interaction with the good energies. The Molecular electrostatic surface potential of the top five compounds states that the interactions were observed mostly in the electropositive region. Finally, the best 5 compounds carried further for molecular dynamics simulations exposed that they were highly stable and no loss of interactions was observed between those complexes.
Hence, from the results, it is evident that the compounds DB00179, Quercetin, Silymarin, Dapagliflozlin and Fisetin could be novel and potent candidates to inhibit the DENV envelope protein.
登革热是一种由蚊媒传播的登革病毒感染引起的主要热带和亚热带国家的公共卫生问题。世界卫生组织将登革热病毒感染列为“被忽视的热带病”。结构蛋白 E 在感染过程中与宿主细胞表面的受体结合，结合指向内吞途径。包膜蛋白的构象变化有助于注入病毒脂质膜，并将病毒基因组递送到细胞质中。迄今为止，尚无特效治疗方法，由于免疫接种和对所有四种血清型的长期保护，开发 DENV 疫苗具有挑战性。因此，鉴定有效的抑制剂将为介导疾病的治疗提供帮助。
我们的研究集中于开发新型有效的抑制剂来抑制登革热病毒包膜蛋白的病毒附着和膜融合。
从蛋白质数据库中检索登革热包膜蛋白的晶体结构，并通过 Schrödinger 进行优化。基于共晶配体的结构基础虚拟筛选与小分子库进行，根据对接得分、相互作用和能量值选择最佳复合物。选择的复合物进一步通过分子动力学模拟进行构象稳定性分析。
从三个数据库中确定了约 55 个分子作为包膜蛋白的潜在配体，对接研究表明，顶级化合物与良好能量具有很强的相互作用。前五个化合物的分子静电表面势能表明，相互作用主要发生在正电性区域。最后，将最好的 5 个化合物进一步进行分子动力学模拟，结果表明它们非常稳定，这些复合物之间没有观察到相互作用的损失。
因此，从结果可以明显看出，化合物 DB00179、槲皮素、水飞蓟素、达格列净和非瑟酮可能是抑制 DENV 包膜蛋白的新型有效候选物。
