Gurusamy Murugaboopathi, Abdul Jainul Fathima
Department of CSE, School of Computing, Kalasalingam Academy of Research and Education, Krishnankoil, Tamilnadu, India.
Research Scholar, Department of CSE, School of Computing, Kalasalingam Academy of Research and Education, Krishnankoil, Tamilnadu, India.
Curr Drug Discov Technol. 2019;16(3):307-314. doi: 10.2174/1570163815666180709155131.
Dengue Fever is a major threatening global health issue caused by a mosquito-borne pathogen. Even though some anti-viral drugs are now available to reduce the disease severity. Still, there is a need of better drug compound to combat with dengue fever. The NS2B/NS3 protease is a major therapeutic drug target for Insilco drug discovery.
MATERIALS & METHODS: Previously, we have performed a pharmacophore features based virtual screening studies, which has led to the identification of ZINC92615064 compound as a potent NS2B/NS3 protease inhibitor and demonstrated its potential to act as anti-dengue drug-like compound using computational approaches. In this present study, the identified lead compound ZINC92615064 has been made to undergo scaffold hopping based novel library generation, and the resulted novel library of compounds has been virtually screened on to NS2B/NS3 protease towards identifying novel proprietary scaffold of compound which is acting as a potent inhibitor for the given drug target of NS2B/NS3.
RESULT & CONCLUSION: A total of 16,847 novel designed compounds library was generated using the scaffold hopping technology based on the structure of the lead compound ZINC92615064. Out of which, compound design no. 3718 has shown the best binding potential with a predicted IC50 value of 417.13 nM along with a permissible range of ADMET properties based on its descriptor values. This NS2B/NS3 protease in complex with compound 3718 was subjected to a rigorous molecular dynamic simulation study to further validate this complex thermodynamic stability, along with the aim to reveal the underlying molecular level interactions and potential mode of action.
登革热是由蚊媒病原体引起的一个重大全球健康威胁问题。尽管现在有一些抗病毒药物可用于降低疾病严重程度。然而，仍需要更好的药物化合物来对抗登革热。NS2B/NS3蛋白酶是基于计算机辅助药物发现的主要治疗药物靶点。
此前，我们进行了基于药效团特征的虚拟筛选研究，该研究导致鉴定出ZINC92615064化合物为一种有效的NS2B/NS3蛋白酶抑制剂，并使用计算方法证明了其作为抗登革热类药物化合物的潜力。在本研究中，已使鉴定出的先导化合物ZINC92615064进行基于骨架跳跃的新型文库生成，并且已对所得的新型化合物文库针对NS2B/NS3蛋白酶进行虚拟筛选，以鉴定作为给定NS2B/NS3药物靶点的有效抑制剂的新型专有化合物骨架。
基于先导化合物ZINC92615064的结构，使用骨架跳跃技术生成了总共16,847个新型设计化合物文库。其中，化合物设计编号3718显示出最佳结合潜力，预测IC50值为417.13 nM，并且基于其描述符值具有可允许的ADMET性质范围。使该与化合物3718复合的NS2B/NS3蛋白酶进行严格的分子动力学模拟研究，以进一步验证该复合物的热力学稳定性，同时旨在揭示潜在的分子水平相互作用和潜在作用模式。
