[目的]利用层级虚拟筛选策略发掘潜在的cGAS-STING通路的干预剂.[方法]根据Human STING蛋白的结构特点,采用 Virtual Screening Workflow 模块进行虚拟筛选,选取 Life Chemicals 50K Diversity Library(LC-50,含5 万个化合物)和MCE Bioactive Compound Library Plus(MCE Library,含1.87万个化合物)作为配体库,并利用Glide模块进行分子对接筛选cGAS-STING通路的干预剂.[结果]分别从两个化合物库中筛选出对接分数绝对值最高的200个化合物,并综合脂水分配系数和拓扑极性表面积选出5个优选先导化合物F6286-0567、F6548-0970、F5098-0465、HY-N7269、HY-N0165,其对接分数分别为-11.097、-10.548、-6.237、-6.146、-5.959.脂水分配系数分别为3.57、3.97、4.08、3.61、3.74.拓扑极性表面积分别为76.29、80.13、75.19、82.19、69.72.[结论]筛选出的干预剂F6286-0567、F6548-0970、F5098-0465、HY-N7269、HY-N0165,在保证与 Human STING 蛋白的结合效果理想的同时,具有更好的细胞膜通过性和脂溶性,可能成为cGAS-STING通路潜在干预剂.
Virtual screening of potential cGAS-STING pathway intervention agents
[Objective]Utilize a hierarchical virtual screening strategy to discover potential interveners for the cGAS-STING pathway.[Method]Based on the structural characteristics of the Human STING protein,the Virtual Screening Workflow module was employed for virtual screening.The Life Chemicals 50K Diversity Library(LC-50,containing 50,000 compounds)and MCE Bioactive Compound Library Plus(MCE Library,containing 18,700 compounds)were selected as ligand libraries.The Glide module was utilized for molecular docking to screen interveners for the cGAS-STING pathway.[Result]The top 200 compounds with the highest absolute docking scores were selected from each of the two compound libraries.Five preferred lead compounds,namely F6286-0567,F6548-0970,F5098-0465,HY-N7269,and HY-N0165,were chosen based on a com-bination of lipophilic water partition coefficient and topological polar surface area.Their docking scores were-11.097,-10.548,-6.237,-6.146,and-5.959,respectively.The lipophilic water partition coefficients were 3.57,3.97,4.08,3.61,and 3.74,while the topological polar surface areas were 76.29,80.13,75.19,82.19,and 69.72.[Conclusion]The screened interveners,F6286-0567,F6548-0970,F5098-0465,HY-N7269,and HY-N0165,exhibit ideal binding effects with the Human STING protein while possessing better cell membrane permeability and lipid solubility.These compounds have the potential to become interveners for the cGAS-STING pathway.
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