Abstract：
The serine/threonine kinase (STK) plays a central role as the primary kinase in poxviruses, directing phosphoryl transfer reactions. Such reactions are pivotal for the activation of certain proteins during viral replication, assembly, and maturation. Therefore, targeting this key protein is anticipated to impede virus replication. In this work, a structural bioinformatics approach was employed to evaluate the potential of drug-like kinase inhibitors in binding to the ATP-binding pocket on the STK of the Mpox virus. Virtual screening of known kinase inhibitors revealed that the top 10 inhibitors exhibited binding affinities ranging from -8.59 to -12.05 kcal/mol. The rescoring of compounds using the deep-learning default model in GNINA was performed to predict accurate binding poses. Subsequently, the top three inhibitors underwent unbiased molecular dynamics (MD) simulations for 100 ns. Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) analysis and Principal Component Analysis (PCA) suggested tepotinib as a competitive inhibitor for Mpox virus STK as evidenced by its binding free energy and the induction of similar conformational behavior of the enzyme. Nevertheless, it is sensible to experimentally test all top 10 compounds, as scoring functions and energy calculations may not consistently align with experimental findings. These insights are poised to provide an attempt to identify an effective inhibitor for the Mpox virus.Communicated by Ramaswamy H. Sarma.
摘要：
丝氨酸/苏氨酸激酶（STK）作为痘病毒的主要激酶发挥着核心作用，指导磷酰基转移反应。这些反应对于病毒复制过程中某些蛋白质的激活至关重要，装配,和成熟。因此,靶向这一关键蛋白预计会阻碍病毒复制。在这项工作中,采用结构生物信息学方法评估了药物样激酶抑制剂与痘病毒STK上的ATP结合口袋结合的潜力.已知激酶抑制剂的虚拟筛选揭示了前10种抑制剂表现出范围为-8.59至-12.05kcal/mol的结合亲和力。使用GNINA中的深度学习默认模型对化合物进行重新评分以预测准确的结合姿势。随后，前三种抑制剂进行了100ns的无偏分子动力学（MD）模拟。分子力学/广义玻恩表面积（MM/GBSA）分析和主成分分析（PCA）表明，特泊替尼是痘病毒STK的竞争性抑制剂，其结合自由能和酶的相似构象行为的诱导证明。然而，实验测试所有前10种化合物是明智的，因为评分函数和能量计算可能与实验结果不一致。这些见解有望为确定有效的痘病毒抑制剂提供尝试。由RamaswamyH.Sarma沟通。
