Oncology R&D, AstraZeneca, Cambridge CB4 0WG, United Kingdom.
Oncology R&D, AstraZeneca, Cambridge CB4 0WG, United Kingdom.
Bioorg Med Chem Lett. 2021 May 1;39:127904. doi: 10.1016/j.bmcl.2021.127904. Epub 2021 Mar 6.
Free Energy Perturbation (FEP) calculations can provide high-confidence predictions of the interaction strength between a ligand and its protein target. We sought to explore a series of triazolopyrimidines which bind to the EED subunit of the PRC2 complex as potential anticancer therapeutics, using FEP calculations to inform compound design. Combining FEP predictions with a late-stage functionalisation (LSF) inspired synthetic approach allowed us to rapidly evaluate structural modifications in a previously unexplored region of the EED binding site. This approach generated a series of novel triazolopyrimidine EED ligands with improved physicochemical properties and which inhibit PRC2 methyltransferase activity in a cancer-relevant G401 cell line.
自由能微扰（FEP）计算可以为配体与其蛋白质靶标的相互作用强度提供高度可信的预测。我们试图探索一系列与 PRC2 复合物的 EED 亚基结合的三唑并嘧啶，将 FEP 计算用于指导化合物设计。将 FEP 预测与后期功能化（LSF）启发的合成方法相结合，使我们能够快速评估 EED 结合位点中以前未探索区域的结构修饰。这种方法生成了一系列新型的三唑并嘧啶 EED 配体，它们具有改善的物理化学性质，并在与癌症相关的 G401 细胞系中抑制 PRC2 甲基转移酶活性。
