In silico identification of potential drug-like molecules against G glycoprotein of Nipah virus by molecular docking, DFT studies, and molecular dynamic simulation

Nipah virus (NiV) is a novel zoonotic pathogen that belongs to the <i>Paramyxovirus</i> family. The pathogen has infected a number of people in countries like Bangladesh, India, Singapore, and Malaysia with high mortality rates. Although the NiV has been classified as a biosafety level four pathogen (BSL-4), there is no drug approved for treatment against it. In this study, the G glycoprotein of the NiV was chosen as an antiviral target. Based on ADMET criteria, BBB- and BBB + group compounds were screened out of the Gold &amp; platinum Asinex library containing 211620 compounds. After careful evaluation, the selected ligands were then virtually screened to identify the potential inhibitors against the G glycoprotein of the NiV through molecular docking, density functional theory (DFT), and molecular dynamic (MD) simulation studies. In our study we identified 5-(1,3-Benzodioxol-5-yl)-2-[(3-fluorobenzyl)sulfanyl]-5,8-dihydropyrido[2,3-d]pyrimidine-4,7(1H,6H)-dione (from BBB- group) and 7,7-Dimethyl-1-(4-methylphenyl)-3-(4-morpholinylcarbonyl)-7,8-dihydro-2,5(1H,6H)-quinolinedione) (from BBB + group) as potential compounds for the prevention and treatment of NiV related diseases. Communicated by Ramaswamy H. Sarma

尼帕病毒（Nipah Virus, NiV）是一种隶属于副黏病毒科（Paramyxovirus）的新型人畜共患病原体。该病原体已在孟加拉国、印度、新加坡及马来西亚等国造成多例感染，致死率极高。尽管NiV已被归类为生物安全四级（biosafety level four, BSL-4）病原体，但目前尚无获批的抗NiV治疗药物。
本研究选取NiV的G糖蛋白作为抗病毒靶点。基于ADMET（吸收、分布、代谢、排泄与毒性）标准，从包含211620种化合物的Gold & platinum Asinex化合物库中筛选出血脑屏障（blood-brain barrier, BBB）阴性（BBB-）与阳性（BBB+）组化合物。经严格评估后，通过分子对接、密度泛函理论（density functional theory, DFT）及分子动力学（molecular dynamic, MD）模拟研究，对筛选得到的配体开展虚拟筛选，以识别靶向NiV G糖蛋白的潜在抑制剂。
本研究鉴定出两款具有开发潜力的化合物：分别为来自BBB-组的5-(1,3-苯并二氧戊环-5-基)-2-[(3-氟苄基)硫烷基]-5,8-二氢吡啶并[2,3-d]嘧啶-4,7(1H,6H)-二酮，以及来自BBB+组的7,7-二甲基-1-(4-甲基苯基)-3-(4-吗啉基羰基)-7,8-二氢-2,5(1H,6H)-喹啉二酮，二者有望用于NiV相关疾病的预防与治疗。本文由Ramaswamy H. Sarma投稿。