A combined bioinformatics and chemoinformatics approach for developing asymmetric bivalent AMPA receptor positive allosteric modulators as neuroprotective agents.
A combined bioinformatics and chemoinformatics approach for developing asymmetric bivalent AMPA receptor positive allosteric modulators as neuroprotective agents.
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DOI：
10.1002/cmdc.201200554
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发表时间：
2013-02
期刊：
影响因子：
3.4
通讯作者：
Zhou, Jia
中科院分区：
文献类型：
--
作者：
Chen, Haijun;Wang, Cheng Z.;Ding, Chunyong;Wild, Christopher;Copits, Bryan;Swanson, Geoffrey T.;Johnson, Kenneth M.;Zhou, Jia
随着药物研发成本的显著上升，临床候选药物的设计应具有更高的成功概率弥合化学和生物空间之间的差距将使药物发现效率发生巨大飞跃，有效利用生物信息学和化学信息学正在成为药物设计的重要组成部分蛋白质或蛋白质配体复合物的晶体结构的数量一直在以近似指数的速度增长分析和比较蛋白质与不同小配体复合物的三级结构可用于指导合理的药物设计，目的是进一步探索化学空间，以识别新的配体片段这些新的片段或支架可以提供一系列更有效的起点，可以进一步发展。一般来说，通过优化这些片段的物理化学性质，包括吸收、溶解、代谢稳定性、血浆蛋白结合、分布、消除、毒理学特征、合成成本和其他药物性质，可以产生一个相当大的化合物文库经鉴定符合Lipinski的类药物“五法则”[6]和Hann和Oprea的类铅标准[7]的化合物，然后被选择进行进一步的分子对接。有前途的化合物可以用合适的算法提取，可以有效和准确地预测它们的构象在这篇论文中，我们采用生物信息学和化学信息学相结合的方法设计和鉴定了一种新型的非对称二价AMPA （α-氨基-3-羟基-5-甲基-4-异唑丙酸）受体阳性变构调节剂，这种调节剂在体外和体内具有显著的预防神经细胞凋亡的效力。
As the cost of research and development in pharmaceutical drugs rises significantly, it is imperative that clinical candidates should be designed with an improved probability of success.[1] Bridging the gap between chemical and biological space would make the quantum leap in the efficiency of drug discovery, and effective utilization of bioinformatics and chemoinformatics is becoming recognized as a valuable component of drug design.[2] The number of crystal structures of proteins or protein-ligand complexes has been growing at an approximately exponential rate.[3] Analysis and comparison of the tertiary structures of a protein complexed with different small ligands can be utilized to guide the rational drug design with the aim of exploring further chemical space to identify novel fragments of ligands.[4] These new fragments or scaffolds may provide a range of more efficient starting points that can be further developed. Generally, a sizable compound library can be generated from such fragments by optimization of their physicochemical properties including absorption, dissolution, metabolic stability, plasma protein binding, distribution, elimination, toxicological profiles, cost of synthesis, and other pharmaceutical properties.[5] The compounds identified to comply with Lipinski’s drug-like “rule of five”[6] and Hann and Oprea’s lead-like criteria [7] are then selected for further molecular docking. The promising compounds can be extracted using suitable algorithms that may efficiently and accurately predict their conformations.[8] In this communication, we applied a combined bioinformatics and chemoinformatics approach to the cost-effective design and identification of novel asymmetric bivalent AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor positive allosteric modulators with remarkable potency in vitro and efficacy in vivo for preventing neuroapotosis.
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影响因子：
5.3
作者：
Adams, SM;Vaccari, JCD;Corriveau, RA
通讯作者：
Corriveau, RA
影响因子：
3.6
作者：
Arai, AC;Kessler, M;Lynch, G
通讯作者：
Lynch, G
影响因子：
120.1
作者：
Leeson, Paul D.;Springthorpe, Brian
通讯作者：
Springthorpe, Brian
影响因子：
120.1
作者：
Hann, Michael M.;Keserue, Gyoergy M.
通讯作者：
Keserue, Gyoergy M.
影响因子：
64.8
作者：
Dobson, CM
通讯作者：
Dobson, CM