基于分子模块组装的新型KCNQ2激动剂设计与合成

doi:10.6023/cjoc202605010

有机化学

研究论文

基于分子模块组装的新型KCNQ2激动剂设计与合成

焦金梦^a,b, 叶潇滢^c,d, 田富云^c,d, 高召兵^c,d, 南发俊^b,e,*, 陈林海^b,e,*

^a安徽中医药大学药学院,安徽合肥,230012;
^b烟台新药创制山东省实验室,中科环渤海药物创新研究院,山东烟台,264100;
^c南京中医药大学新中药学院,江苏南京,210023;
^d中科中山药物创新研究院,广东中山,528400;
^e中国科学院上海药物研究所,上海浦东,201203

收稿日期:2026-07-29 修回日期:2026-08-17
基金资助:
国家科技创新2030重大项目（No. 2021ZD0200900）、国家自然科学基金（No. 22477106）、山东省泰山学者青年专家项目（No. tsqn202408314）及烟台市省级以上领军人才专项资助项目.

Design and Synthesis of Novel KCNQ2 Agonists Based on Molecular Module Assembly

Jinmeng Jiao^a,b, Xiaoying Ye^c,d, Fuyun Tian^c,d, Zhaobing Gao^c,d, Fajun Nan^b,e,*, Linhai Chen^b,e,*

^a School of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012;
^b Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264100;
^c School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023;
^d Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400;
^e Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 210023

Received:2026-07-29 Revised:2026-08-17
Contact: *E-mail: fjnan@simm.ac.cn; lhchen@simm.ac.cn
Supported by:
National Science and Technology Innovation 2030 Major Program (2021ZD0200900), the National Natural Science Foundation of China (No. 22477106), the Taishan Scholars Program (No. tsqn202408314), and the Special Foundation of Yantai for Leading Talents above Provincial Level.

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摘要/Abstract

本文采用分子模块组装策略,以靶向电压门控钾通道Q亚家族 (Potassium voltage-gated channel subfamily Q, KCNQ) 的临床候选药物派恩加滨 (HN37) 为模版进行结构优化。研究首先基于多构象分子对接与多元线性回归建立了活性预测模型;同时,通过子结构检索获取多样化的分子砌块,利用Buchwald-Hartwig反应进行模块化组装,构建了兼具高合成可及性与结构新颖性的虚拟化合物库。随后,结合类药性评价和活性预测模型对库内分子进行分级筛选,识别出一批优选结构。在此基础上,合成了24个目标化合物并采用全细胞膜片钳技术评估其激动活性。实验结果显示,共有6个化合物在100 nM浓度下可显著激动KCNQ2通道,并初步明确了构效关系。其中化合物3和4表现出良好的KCNQ2激动活性、KCNQ通道亚型选择性及代谢稳定性。本研究将基于模块组装的分子设计、分级虚拟筛选与实验验证相结合,发现了一批具有潜力的KCNQ2激动剂,为后续的结构优化奠定了基础。

关键词: KCNQ2激动剂, 派恩加滨, 结构优化, 活性预测模型, 分子模块组装

In this study, a molecular module assembly strategy was employed for the structural optimization of pynegabine (HN37), a clinical candidate targeting the potassium voltage-gated channel subfamily Q (KCNQ). First, an activity prediction model was established based on multi-conformation molecular docking and multiple linear regression. Simultaneously, a virtual compound library with high synthetic accessibility and structural novelty was constructed via modular assembly based on the Buchwald-Hartwig reaction, utilizing diverse building blocks acquired through substructure searches. Subsequently, a hierarchical virtual screening workflow—combining drug-likeness evaluation and established activity prediction model—was applied to identify a set of prioritized structures. On this basis, 24 target compounds were synthesized and evaluated using whole-cell patch-clamp electrophysiology. Experimental results demonstrated that 6 compounds exhibited significant agonistic activity against the KCNQ2 channel at 100 nM, with the structure-activity relationships (SAR) preliminary elucidated. Among them, compounds 3 and 4 showed favorable KCNQ2 agonistic activity, subtype selectivity for KCNQ channels, and metabolic stability. By integrating module-assembly-based molecular design, hierarchical virtual screening, and experimental validation, this work identifies a series of promising KCNQ2 agonists and paves the way for subsequent optimization.

Key words: KCNQ2 agonists, pynegabine, structural optimization, activity-prediction model, molecular module assembly

引用此文

焦金梦, 叶潇滢, 田富云, 高召兵, 南发俊, 陈林海. 基于分子模块组装的新型KCNQ2激动剂设计与合成[J]. 有机化学, doi: 10.6023/cjoc202605010.

Jinmeng Jiao, Xiaoying Ye, Fuyun Tian, Zhaobing Gao, Fajun Nan, Linhai Chen. Design and Synthesis of Novel KCNQ2 Agonists Based on Molecular Module Assembly[J]. Chinese Journal of Organic Chemistry, doi: 10.6023/cjoc202605010.

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基于分子模块组装的新型KCNQ2激动剂设计与合成

Design and Synthesis of Novel KCNQ2 Agonists Based on Molecular Module Assembly

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