Physics-based Design of Bifunctional Degraders, Virtual 基于物理理论设计的双功能降解剂,网络讲座录制


Dr. Jianxin Duan
Fellow, Applications Science


具有两个配体和一个 Linker 的双功能 分子能够结合E3连接酶与靶蛋白,从而促使靶蛋白降解。双功能降解剂的分子设计仍面临许多挑战:1)优化蛋白配体(warhead)与 Linker 的连接点,避免对靶点结合产生干扰;2)鉴于复杂的结构,优化降解剂的结合效力;3)三元组结构模型的预测。以上的挑战中第一项与小分子设计相同,十分适合采用 FEP+。本次网络讲座,我们将展示如何将基于物理理论的模拟(例如增强采样和 FEP)应用于第2个和第3个挑战。

Bifunctional molecules with two ligands and a linker are able to recruit an E3 ligase to the target protein, leading to the degradation of the target protein. The design of bifunctional degraders is facing a number of challenges; 1) optimization of the warhead ligands and the linker attachment points to avoid disruption of on target binding; 2) given the complex structure, optimization of the binding potency of the degraders; 3) prediction of ternary structure models. The first challenge is essentially the same as small molecule design which is well suited for FEP+. In this Webinar we will show how physics-based simulations such as enhanced sampling and FEP can be applied to the second and third challenges.