We developed MaxQsaring,a novel universal framework integrating molecular descriptors,fingerprints,and deep-learning pretrained representations,to predict the properties of compounds.Applied to a case study of human e...We developed MaxQsaring,a novel universal framework integrating molecular descriptors,fingerprints,and deep-learning pretrained representations,to predict the properties of compounds.Applied to a case study of human ether-à-go-go-related gene(hERG)blockage prediction,MaxQsaring achieved state-of-the-art performance on two challenging external datasets through automatic optimal feature combinations,and successfully identified top 10 important interpretable features that could be used to model a high-accuracy decision tree.The models'predictions align well with empirical hERG optimization strategies,demonstrating their interpretability for practical utilities.Deep learning pre-trained representations have been demonstrated to exert a moderate influence on enhancing the performance of predictive models.Nevertheless,their impact on augmenting the generalizability of these models,particularly when applied to compounds possessing novel scaffolds,appears to be comparatively minimal.MaxQsaring excelled in the Therapeutics Data Commons(TDC)benchmarks,ranking first in 19 out of 22 tasks,showcasing its potential for universal accurate compound property prediction to facilitate a high success rate of early drug discovery,which is still a formidable challenge.展开更多
目的研究大蒜素对HEK293细胞HERG电流的作用,探讨其抗心律失常的可能机制。方法采用瞬时转染的方法,将HERG通道质粒转入HEK293细胞上,应用细胞外局部灌流法于膜片钳高阻抗封接形成后给予大蒜素,使其终浓度为30μmol/L。室温下,采用全细...目的研究大蒜素对HEK293细胞HERG电流的作用,探讨其抗心律失常的可能机制。方法采用瞬时转染的方法,将HERG通道质粒转入HEK293细胞上,应用细胞外局部灌流法于膜片钳高阻抗封接形成后给予大蒜素,使其终浓度为30μmol/L。室温下,采用全细胞膜片钳技术在电压钳形模式下记录电流和门控动力学,观察大蒜素对HERG电流的作用。结果 30μmol/L大蒜素对正常大鼠心室肌细胞HERG电流有显著的阻滞效应,使其尾电流密度由73.5±4.3 p A/p F降低至42.1±3.6 p A/p F(P<0.01,n=14)。其作用呈浓度依赖性。半数抑制浓度为34.74μmol/L,Hill系数为1.01。大蒜素可使HERG的电流-电压曲线降低,且随着去极化电位的增加,作用更加明显,提示其作用具有电压依赖性,门控机制研究发现大蒜素可以使通道激活曲线向更正的方向移动,进而延迟激活;使通道稳态失活更负的方向移动,导致失活加速。同时,使通道灭活的慢时间常数缩短,从而加速通道的灭活。结论大蒜素抑制HEK293细胞上HERG电流,提示这可能是其治疗心律失常的细胞电生理基础。展开更多
快速延迟整流钾电流(rapidly activating com ponent of delayed rectifier potassium current,IKr)在心肌动作电位复极化过程中发挥重要作用。HERG基因编码心脏快速延迟整流钾通道的α亚基,HERG基因突变导致遗传性长QT间期综合征(long ...快速延迟整流钾电流(rapidly activating com ponent of delayed rectifier potassium current,IKr)在心肌动作电位复极化过程中发挥重要作用。HERG基因编码心脏快速延迟整流钾通道的α亚基,HERG基因突变导致遗传性长QT间期综合征(long QT syndrome,LQTS),另外IKr/HERG通道是绝大多数能引起心脏QT间期延长药物的作用靶标,其他一些化学结构不同的药物也可阻断该通道,引起QT间期延长,甚至发展成获得性心律失常。本文从门控机制及功能、HERG通道相关的心律失常、药物与通道相互作用机制、优化通道靶点的策略等四个方面综述IKr/HERG通道在抗心律失常方面的最新研究进展。展开更多
基金supported in part by the National Key R&D Program of China(Grant No.:2023YFF1205103)the National Natural Science Foundation of China(Grant No.:220330010)the Anhui’s Plans for Major Provincial Science&Technology Projects,China(Grant No.:202303a07020009).
文摘We developed MaxQsaring,a novel universal framework integrating molecular descriptors,fingerprints,and deep-learning pretrained representations,to predict the properties of compounds.Applied to a case study of human ether-à-go-go-related gene(hERG)blockage prediction,MaxQsaring achieved state-of-the-art performance on two challenging external datasets through automatic optimal feature combinations,and successfully identified top 10 important interpretable features that could be used to model a high-accuracy decision tree.The models'predictions align well with empirical hERG optimization strategies,demonstrating their interpretability for practical utilities.Deep learning pre-trained representations have been demonstrated to exert a moderate influence on enhancing the performance of predictive models.Nevertheless,their impact on augmenting the generalizability of these models,particularly when applied to compounds possessing novel scaffolds,appears to be comparatively minimal.MaxQsaring excelled in the Therapeutics Data Commons(TDC)benchmarks,ranking first in 19 out of 22 tasks,showcasing its potential for universal accurate compound property prediction to facilitate a high success rate of early drug discovery,which is still a formidable challenge.
文摘目的研究大蒜素对HEK293细胞HERG电流的作用,探讨其抗心律失常的可能机制。方法采用瞬时转染的方法,将HERG通道质粒转入HEK293细胞上,应用细胞外局部灌流法于膜片钳高阻抗封接形成后给予大蒜素,使其终浓度为30μmol/L。室温下,采用全细胞膜片钳技术在电压钳形模式下记录电流和门控动力学,观察大蒜素对HERG电流的作用。结果 30μmol/L大蒜素对正常大鼠心室肌细胞HERG电流有显著的阻滞效应,使其尾电流密度由73.5±4.3 p A/p F降低至42.1±3.6 p A/p F(P<0.01,n=14)。其作用呈浓度依赖性。半数抑制浓度为34.74μmol/L,Hill系数为1.01。大蒜素可使HERG的电流-电压曲线降低,且随着去极化电位的增加,作用更加明显,提示其作用具有电压依赖性,门控机制研究发现大蒜素可以使通道激活曲线向更正的方向移动,进而延迟激活;使通道稳态失活更负的方向移动,导致失活加速。同时,使通道灭活的慢时间常数缩短,从而加速通道的灭活。结论大蒜素抑制HEK293细胞上HERG电流,提示这可能是其治疗心律失常的细胞电生理基础。
