裂谷热病毒(RVFV)是病毒性人畜共患病的病原体,在家畜和野生反刍动物中引起重大的临床负担。该病毒的主要爆发发生在牲畜中,受污染的动物产品或节肢动物媒介可以将病毒传播给人类。RVFV的病毒RNA依赖性RNA聚合酶(RdRp;L蛋白)负责病毒复制,因此是一种吸引人的药物靶标,因为没有针对该病毒的有效和特异性疫苗可用。目前的研究报道了通过深入同源建模对RVFV-L蛋白的结构阐明,因为尚无晶体结构。分析了已知的有效L蛋白抑制剂的抑制结合模式。根据结果,对Selleckchem核苷类似物库(156种化合物)进行了进一步的基于分子对接的虚拟筛选,以寻找针对RVFVL蛋白的潜在新抑制剂.ADME(吸收,Distribution,代谢,和排泄),并对这些化合物进行了毒性分析。此外,通过50ns分子动力学(MD)模拟,然后进行MM/PBSA结合自由能计算,证实了已鉴定化合物的结合机理和稳定性。同源性建模确定了L蛋白的稳定多结构域结构。对已知L蛋白抑制剂的分析,包括莫能菌素,霉酚酸,还有利巴韦林,提供对结合机制的见解,并揭示L蛋白结合口袋的关键残基。筛选结果显示,前三个化合物,A-317491,Khasianine,和VER155008在L蛋白结合口袋处表现出高亲和力。ADME分析显示这些化合物具有良好的药效学和药代动力学特征。此外,MD模拟和结合自由能分析证明了潜在化合物与L蛋白的结合稳定性。简而言之,本研究确定了可能有助于合理设计RVFVL蛋白的新型抑制剂作为抗RVFV药物的潜在化合物。
Rift valley fever virus (
RVFV) is the causative agent of a viral zoonosis that causes a significant clinical burden in domestic and wild ruminants. Major outbreaks of the virus occur in livestock, and contaminated animal products or arthropod vectors can transmit the virus to humans. The viral RNA-dependent RNA polymerase (RdRp; L protein) of the
RVFV is responsible for viral replication and is thus an appealing drug target because no effective and specific vaccine against this virus is available. The current study reported the structural elucidation of the
RVFV-L protein by in-depth homology modeling since no crystal structure is available yet. The inhibitory binding modes of known potent L protein inhibitors were analyzed. Based on the results, further molecular docking-based virtual screening of Selleckchem Nucleoside Analogue Library (156 compounds) was performed to find potential new inhibitors against the
RVFV L protein. ADME (Absorption, Distribution, Metabolism, and Excretion) and toxicity analysis of these compounds was also performed. Besides, the binding mechanism and stability of identified compounds were confirmed by a 50 ns molecular dynamic (MD) simulation followed by MM/PBSA binding free energy calculations. Homology modeling determined a stable multi-domain structure of L protein. An analysis of known L protein inhibitors, including Monensin, Mycophenolic acid, and Ribavirin, provide insights into the binding mechanism and reveals key residues of the L protein binding pocket. The screening results revealed that the top three compounds, A-317491, Khasianine, and VER155008, exhibited a high affinity at the L protein binding pocket. ADME analysis revealed good pharmacodynamics and pharmacokinetic profiles of these compounds. Furthermore, MD simulation and binding free energy analysis endorsed the binding stability of potential compounds with L protein. In a nutshell, the present study determined potential compounds that may aid in the rational design of novel inhibitors of the RVFV L protein as anti-
RVFV drugs.