Zhang Yuqi, Vass Marton, Shi Da, Abualrous Esam, Chambers Jennifer M, Chopra Nikita, Higgs Christopher, Kasavajhala Koushik, Li Hubert, Nandekar Prajwal, Sato Hideyuki, Miller Edward B, Repasky Matthew P, Jerome Steven V
Schrödinger Inc., 9868 Scranton Road, Suite3200, San Diego, California 92121, United States.
Schrödinger Technologies Limited, Nine Hills Road, Cambridge CB2 1GE, United Kingdom.
J Chem Inf Model. 2023 Mar 27;63(6):1656-1667. doi: 10.1021/acs.jcim.2c01219. Epub 2023 Mar 10.
The recently developed AlphaFold2 (AF2) algorithm predicts proteins' 3D structures from amino acid sequences. The open AlphaFold protein structure database covers the complete human proteome. Using an industry-leading molecular docking method (Glide), we investigated the virtual screening performance of 37 common drug targets, each with an AF2 structure and known and structures from the DUD-E data set. In a subset of 27 targets where the AF2 structures are suitable for refinement, the AF2 structures show comparable early enrichment of known active compounds (avg. EF 1%: 13.0) to structures (avg. EF 1%: 11.4) while falling behind early enrichment of the structures (avg. EF 1%: 24.2). With an induced-fit protocol (IFD-MD), we can refine the AF2 structures using an aligned known binding ligand as the template to improve the performance in structure-based virtual screening (avg. EF 1%: 18.9). Glide-generated docking poses of known binding ligands can also be used as templates for IFD-MD, achieving similar improvements (avg. EF 1% 18.0). Thus, with proper preparation and refinement, AF2 structures show considerable promise for hit identification.
最近开发的AlphaFold2（AF2）算法可根据氨基酸序列预测蛋白质的三维结构。开放的AlphaFold蛋白质结构数据库涵盖了完整的人类蛋白质组。我们使用业界领先的分子对接方法（Glide），研究了37个常见药物靶点的虚拟筛选性能，每个靶点都有AF2结构以及来自DUD-E数据集的已知结构。在27个AF2结构适合优化的靶点子集中，AF2结构显示出与已知活性化合物的早期富集程度相当（平均1%富集因子：13.0），与已知结构相当（平均1%富集因子：11.4），但落后于已知结构的早期富集程度（平均1%富集因子：24.2）。通过诱导契合协议（IFD-MD），我们可以使用对齐的已知结合配体作为模板来优化AF2结构，以提高基于结构的虚拟筛选性能（平均1%富集因子：18.9）。Glide生成的已知结合配体的对接姿势也可用作IFD-MD的模板，实现类似的改进（平均1%富集因子：18.0）。因此，经过适当的准备和优化，AF2结构在命中物识别方面显示出相当大的前景。
