Graduate School of New Drug Discovery and Development, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 34134, Korea.
Pharos iBio Co., Ltd. #1408, 38 Heungan-daero 427, Dongan-gu, Anyang-si 14059, Korea.
Int J Mol Sci. 2022 Mar 19;23(6):3337. doi: 10.3390/ijms23063337.
The intrinsic inductive properties of atoms or functional groups depend on the chemical properties of either electron-withdrawing groups (EWGs) or electron-donating groups (EDGs). This study aimed to evaluate in silico methods to determine whether changes in chemical properties of the compound by single atomic substitution affect the biological activity of target proteins and whether the results depend on the properties of the functional groups. We found an imidazo[4,5-b]pyridine-based PAK4 inhibitor, compound , as an initial hit compound with the well-defined binding mode for PAK4. In this study, we used both experimental and in silico methods to investigate the effect of atomic substitution on biological activity to optimize the initial hit compound. In biological assays, in the case of EWG, as the size of the halogen atom became smaller and the electronegativity increased, the biological activity IC value ranged from 5150 nM to inactive; in the case of EDG, biological activity was inactive. Furthermore, we analyzed the interactions of PAK4 with compounds, focusing on the hinge region residues, L398 and E399, and gatekeeper residues, M395 and K350, of the PAK4 protein using molecular docking studies and fragment molecular orbital (FMO) methods to determine the differences between the effect of EWG and EDG on the activity of target proteins. These results of the docking score and binding energy did not explain the differences in biological activity. However, the pair-interaction energy obtained from the results of the FMO method indicated that there was a difference in the interaction energy between the EWG and EDG in the hinge region residues, L398 and E399, as well as in M395 and K350. The two groups with different properties exhibited opposite electrostatic energy and charge transfer energy between L398 and E399. Additionally, we investigated the electron distribution of the parts interacting with the hinge region by visualizing the molecular electrostatic potential (MEP) surface of the compounds. In conclusion, we described the properties of functional groups that affect biological activity using an in silico method, FMO.
原子或官能团的固有感应性质取决于吸电子基团 (EWG) 或供电子基团 (EDG) 的化学性质。本研究旨在评估计算方法，以确定化合物的化学性质通过单个原子取代而发生变化是否会影响靶蛋白的生物活性，以及结果是否取决于官能团的性质。我们发现一种基于咪唑并[4,5-b]吡啶的 PAK4 抑制剂，化合物 ，作为具有明确 PAK4 结合模式的初始命中化合物。在这项研究中，我们使用实验和计算方法来研究原子取代对生物活性的影响，以优化初始命中化合物。在生物测定中，对于 EWG，随着卤原子的尺寸变小和电负性增加，生物活性 IC 值范围为 5150 nM 至无活性；对于 EDG，生物活性无活性。此外，我们使用分子对接研究和片段分子轨道 (FMO) 方法分析了 PAK4 与化合物的相互作用，重点是 PAK4 蛋白的 hinge 区域残基 L398 和 E399 以及 gatekeeper 残基 M395 和 K350，以确定 EWG 和 EDG 对靶蛋白活性的影响之间的差异。对接得分和结合能的这些结果并不能解释生物活性的差异。然而，从 FMO 方法的结果中获得的偶极子相互作用能表明，在 hinge 区域残基 L398 和 E399 以及 M395 和 K350 中，EWG 和 EDG 之间的相互作用能存在差异。这两组具有不同性质的基团在 L398 和 E399 之间表现出相反的静电能和电荷转移能。此外，我们通过可视化化合物的分子静电势 (MEP) 表面研究了与 hinge 区域相互作用的部分的电子分布。总之，我们使用计算方法 FMO 描述了影响生物活性的官能团的性质。
