Department of Pharmaceutical and Pharmacological Sciences, Rega Institute for Medical Research, Medicinal Chemistry, University of Leuven, Leuven, Belgium.
Center for Research in Molecular Medicine (CRiMM), The University of Lahore, Lahore, Pakistan.
Sci Rep. 2019 May 2;9(1):6809. doi: 10.1038/s41598-019-43129-2.
The Crimean-Congo Hemorrhagic Fever virus (CCHFV) is a segmented negative single-stranded RNA virus (-ssRNA) which causes severe hemorrhagic fever in humans with a mortality rate of ~50%. To date, no vaccine has been approved. Treatment is limited to supportive care with few investigational drugs in practice. Previous studies have identified viral RNA dependent RNA Polymerase (RdRp) as a potential drug target due to its significant role in viral replication and transcription. Since no crystal structure is available yet, we report the structural elucidation of CCHFV-RdRp by in-depth homology modeling. Even with low sequence identity, the generated model suggests a similar overall structure as previously reported RdRps. More specifically, the model suggests the presence of structural/functional conserved RdRp motifs for polymerase function, the configuration of uniform spatial arrangement of core RdRp sub-domains, and predicted positively charged entry/exit tunnels, as seen in sNSV polymerases. Extensive pharmacophore modeling based on per-residue energy contribution with investigational drugs allowed the concise mapping of pharmacophoric features and identified potential hits. The combination of pharmacophoric features with interaction energy analysis revealed functionally important residues in the conserved motifs together with in silico predicted common inhibitory binding modes with highly potent reference compounds.
克里米亚-刚果出血热病毒（CCHFV）是一种分段的负单链 RNA 病毒（-ssRNA），可导致人类严重出血热，死亡率约为 50%。迄今为止，尚未批准任何疫苗。治疗方法仅限于支持性护理，实际上只有少数研究性药物。先前的研究已经确定病毒 RNA 依赖性 RNA 聚合酶（RdRp）是一种潜在的药物靶点，因为它在病毒复制和转录中具有重要作用。由于目前尚无晶体结构，我们通过深入的同源建模报告了 CCHFV-RdRp 的结构阐明。即使序列同一性较低，生成的模型也表明与先前报道的 RdRps 具有相似的整体结构。更具体地说，该模型表明存在用于聚合酶功能的结构/功能保守的 RdRp 基序、核心 RdRp 亚结构域均匀空间排列的配置以及预测的带正电荷的进入/退出隧道，如 sNSV 聚合酶中所见。基于与研究性药物的残基能量贡献的广泛药效团建模允许简洁地映射药效特征，并确定潜在的命中。将药效特征与相互作用能分析相结合，揭示了保守基序中具有功能重要性的残基，以及与高活性参考化合物的计算机预测的常见抑制结合模式。
