Molecular glues can specifically induce aggregation between two or more proteins to modulate biological functions.In recent years,molecular glues have been widely used as protein degraders.In addition,however,molecula...Molecular glues can specifically induce aggregation between two or more proteins to modulate biological functions.In recent years,molecular glues have been widely used as protein degraders.In addition,however,molecular glues play a variety of vital roles,such as complex stabilization,interactome modulation and transporter inhibition,enabling challenging therapeutic targets to be druggable and offering an exciting novel approach for drug discovery.Since most molecular glues are identified serendipitously,exploration of their systematic discovery and rational design are important.In this review,representative examples of molecular glues with various physiological functions are divided into those mediating homo-dimerization,homo-polymerization and hetero-dimerization according to their aggregation modes,and we attempt to elucidate their mechanisms of action.In particular,we aim to highlight some biochemical techniques typically exploited within these representative studies and classify them in terms of three stages of molecular glue development:starting point,optimization and identification.展开更多
本文在Blasone研究工作的基础上,进一步提出了基于马尔科夫链-蒙特卡洛算法的改进通用似然不确定性估计方法(Markov Chain-Monte Carlo based Modified Generalized Likelihood Uncertainty Estimation,MMGLUE)。该方法结合近年来被广...本文在Blasone研究工作的基础上,进一步提出了基于马尔科夫链-蒙特卡洛算法的改进通用似然不确定性估计方法(Markov Chain-Monte Carlo based Modified Generalized Likelihood Uncertainty Estimation,MMGLUE)。该方法结合近年来被广泛用于推求参数后验分布的MCMC方法,对基于Monte Carlo随机取样方法的传统GLUE方法进行改进,并以预测区间性质最优为标准,对可行参数组阈值进行判断与选择,提出了衡量预测区间对称性的标准,并就预测区间性质与可行参数组个数的相关关系进行了探索。在汉江玉带河流域的实例研究证明,MMGLUE方法较传统的GLUE方法能够推求出性质更为优良的预测区间,从而更真实合理地反映水文模型的不确定性。展开更多
基金supported from the National Natural Science Foundation of China (Nos. 82173672, 82173679, 81903446 and 81973167, China)Natural Science Foundation of Jiangsu Province (BK20190564, China)+1 种基金“Double First-Class” University project of China Pharmaceutical University (CPU2018GY04, China)Free exploration basic research project of Shenzhen Virtual University Park (2021Szvup162, China) for financial support
文摘Molecular glues can specifically induce aggregation between two or more proteins to modulate biological functions.In recent years,molecular glues have been widely used as protein degraders.In addition,however,molecular glues play a variety of vital roles,such as complex stabilization,interactome modulation and transporter inhibition,enabling challenging therapeutic targets to be druggable and offering an exciting novel approach for drug discovery.Since most molecular glues are identified serendipitously,exploration of their systematic discovery and rational design are important.In this review,representative examples of molecular glues with various physiological functions are divided into those mediating homo-dimerization,homo-polymerization and hetero-dimerization according to their aggregation modes,and we attempt to elucidate their mechanisms of action.In particular,we aim to highlight some biochemical techniques typically exploited within these representative studies and classify them in terms of three stages of molecular glue development:starting point,optimization and identification.
文摘本文在Blasone研究工作的基础上,进一步提出了基于马尔科夫链-蒙特卡洛算法的改进通用似然不确定性估计方法(Markov Chain-Monte Carlo based Modified Generalized Likelihood Uncertainty Estimation,MMGLUE)。该方法结合近年来被广泛用于推求参数后验分布的MCMC方法,对基于Monte Carlo随机取样方法的传统GLUE方法进行改进,并以预测区间性质最优为标准,对可行参数组阈值进行判断与选择,提出了衡量预测区间对称性的标准,并就预测区间性质与可行参数组个数的相关关系进行了探索。在汉江玉带河流域的实例研究证明,MMGLUE方法较传统的GLUE方法能够推求出性质更为优良的预测区间,从而更真实合理地反映水文模型的不确定性。
