Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009 Jiangsu, P. R. China.
Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058 Zhejiang, P. R. China.
J Chem Inf Model. 2024 Oct 14;64(19):7666-7678. doi: 10.1021/acs.jcim.4c01227. Epub 2024 Oct 3.
Proteolytic targeting chimeras (PROTACs), as an emerging type of drug, function by proximity-based modalities that narrow the distance between a target protein and the E3 ubiquitin ligase to facilitate the ubiquitination labeling of the target protein for degradation. Although it is evidenced that the cooperativity of the PROTAC ternary interaction is one of the key factors affecting the degradation rate of a target protein, PROTAC design utilizing this indicator is still challenging because of the complicated/flexible interactions in a target-PROTAC-E3 ternary system. Therefore, developing reliable and practicable computational methods is of great interest for PROTAC design. Hence, in this study, we investigate the feasibility of using the end-point binding free energy calculation method, represented by molecular mechanics/Poisson-Boltzmann (generalized-Born) surface area (MM/PB(GB)SA), for characterizing cooperativity (including the stabilization and hook effects) of the PROTAC systems. The result shows that MM/GBSA is a good predictor in characterizing these effects under a relatively long molecular dynamics adjustment (50-100 ns) and low dielectric constant (ε = 1), with the Pearson correlation coefficient () > 0.5 and 0.6 for the stabilization and hook effect, respectively. This study provides a feasible strategy for characterizing the cooperativity of the PROTAC systems, facilitating the rational design of PROTAC molecules.
蛋白水解靶向嵌合体（PROTACs）作为一种新兴的药物，通过基于邻近性的模式发挥作用，这种模式缩小了靶蛋白与 E3 泛素连接酶之间的距离，从而促进靶蛋白的泛素化标记和降解。虽然已经有证据表明，PROTAC 三元相互作用的协同性是影响靶蛋白降解速率的关键因素之一，但由于靶标-PROTAC-E3 三元体系中存在复杂/灵活的相互作用，利用这一指标进行 PROTAC 设计仍然具有挑战性。因此，开发可靠和实用的计算方法对于 PROTAC 设计具有重要意义。因此，在本研究中，我们研究了使用终点结合自由能计算方法（以分子力学/泊松-玻尔兹曼（广义 Born）表面积（MM/PB（GB）SA）表示）来表征 PROTAC 体系协同性（包括稳定化和钩效）的可行性。结果表明，在相对较长的分子动力学调整（50-100ns）和低介电常数（ε=1）下，MM/GBSA 是一种很好的预测方法，对这些效应的 Pearson 相关系数（r）分别大于 0.5 和 0.6。本研究为表征 PROTAC 体系的协同性提供了一种可行的策略，有助于合理设计 PROTAC 分子。
