9D6H の概要
| エントリーDOI | 10.2210/pdb9d6h/pdb |
| 分子名称 | Non-structural protein 3, (2R)-3-methyl-2-[(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]butan-1-ol, DIMETHYL SULFOXIDE, ... (5 entities in total) |
| 機能のキーワード | macrodomain, adp-ribose, sars-cov-2, fragment-based drug discovery, viral protein |
| 由来する生物種 | Severe acute respiratory syndrome coronavirus 2 |
| タンパク質・核酸の鎖数 | 2 |
| 化学式量合計 | 36769.52 |
| 構造登録者 | |
| 主引用文献 | Correy, G.J.,Rachman, M.M.,Togo, T.,Gahbauer, S.,Doruk, Y.U.,Stevens, M.G.V.,Jaishankar, P.,Kelley, B.,Goldman, B.,Schmidt, M.,Kramer, T.,Radchenko, D.S.,Moroz, Y.S.,Ashworth, A.,Riley, P.,Shoichet, B.K.,Renslo, A.R.,Walters, W.P.,Fraser, J.S. Exploration of structure-activity relationships for the SARS-CoV-2 macrodomain from shape-based fragment linking and active learning. Sci Adv, 11:eads7187-eads7187, 2025 Cited by PubMed Abstract: The macrodomain of severe acute respiratory syndrome coronavirus 2 nonstructural protein 3 is required for viral pathogenesis and is an emerging antiviral target. We previously performed an x-ray crystallography-based fragment screen and found submicromolar inhibitors by fragment linking. However, these compounds had poor membrane permeability and liabilities that complicated optimization. Here, we developed a shape-based virtual screening pipeline-FrankenROCS. We screened the Enamine high-throughput collection of 2.1 million compounds, selecting 39 compounds for testing, with the most potent binding with a 130 μM median inhibitory concentration (IC). We then paired FrankenROCS with an active learning algorithm (Thompson sampling) to efficiently search the Enamine REAL database of 22 billion molecules, testing 32 compounds with the most potent binding with a 220 μM IC. Further optimization led to analogs with IC values better than 10 μM. This lead series has improved membrane permeability and is poised for optimization. FrankenROCS is a scalable method for fragment linking to exploit synthesis-on-demand libraries. PubMed: 40435250DOI: 10.1126/sciadv.ads7187 主引用文献が同じPDBエントリー |
| 実験手法 | X-RAY DIFFRACTION (1.02 Å) |
構造検証レポート
検証レポート(詳細版)
をダウンロード
をダウンロード
