恰当地评估药物不良反应（ADRs）在用药安全和新药研发中都起着至关重要的作用。然而,由于对药物不良反应分子机制的认识有限,传统的药物毒性评估技术大多局限于对急性毒性或个别严重ADRs的预测,或是缺乏对预测结果的量化描述。近年来,生物信息学对药物毒理学研究的影响日益增强,将药物安全性评估带入了新纪元。在此,我们介绍一个新颖的用于在药物研发早期阶段快速量化评估临床ADRs和药物安全性的在线软件——Adverse Drug Reaction Alert（ADRAlert）。ADRAlert构建于一个精确训练的基于全基因组基因-ADR关联网络的朴素贝叶斯模型,其在内部验证和外部验证中都获得了大于88%的平均ADR检出率。它允许输入配体调控的基因关系,并输出该配体可能引起的潜在临床ADRs及其频率。同时,根据估计的ADR频率及ADR严重等级计算该配体的毒性分数。总而言之,ADRAlert为临床潜在药物毒性的评估提供了一种经济且有效的方式。
GPCR plays a key role in signal transduction between intracellular and extracellular and has been important drug ***,many experimental studies found that GPCRs can form the dimer or oligomer,which are another potentia...
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GPCR plays a key role in signal transduction between intracellular and extracellular and has been important drug ***,many experimental studies found that GPCRs can form the dimer or oligomer,which are another potential functional units besides their ***,there have been absent of knowledge about structures,dynamics and functions of GPCR ***,we,herein,we used the Elastic Network Model(ENM)and Protein Structure Network(PSN)to study the three GPCR dimers(viz.,CXCR4,κ-opioid R,β1AR)with different interfaces according to their basic topologic *** low-frequency modes from ENM indicate that the three GPCR monomers commonly present an antisymmetric rotation between extracelluar and intracellar motifs while their dimers exhibit an asymmetrical fluctuation between the two protomers,which should contribute to the negative cooperation between the two protomers and the asymmetric activation of GPCR dimers reported by *** reveal that the dimerization can reduce informational flows characterized by the communication pathways between intracellular and extracellular,resulted from weakening restricts between *** comparison between the monomer and protomer of the dimer shows that the TM1-TM2-H8 interface play more significant role in influencing the dynamics of the promoter with respect to TM5-TM6 ***,the most significant effect of the dimerization is observed forκ-opioid with TM1-TM2-H8 interface.B1AR also exhibits more difference between its monomer and dimer than CXCR4 due to larger contact areas in the interface ofβ1AR,although they have same TM4-TM5 *** observations from the work could provide valuable information for understanding the structure and function of GPCR dimers.
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