新型视黄酸受体激动剂结构的计算机模拟发现
In silico discovery of novel retinoic acid receptor agonist structures.
作者信息
Schapira M, Raaka B M, Samuels H H, Abagyan R
机构信息
Structural Biology, Skirball Institute of Biomolecular Medicine, New York, USA.
出版信息
BMC Struct Biol. 2001;1:1. doi: 10.1186/1472-6807-1-1. Epub 2001 Jun 4.
BACKGROUND
Several Retinoic Acid Receptors (RAR) agonists have therapeutic activity against a variety of cancer types; however, unacceptable toxicity profiles have hindered the development of drugs. RAR agonists presenting novel structural and chemical features could therefore open new avenues for the discovery of leads against breast, lung and prostate cancer or leukemia.
RESULTS
We have analysed the induced fit of the active site residues upon binding of a known ligand. The derived binding site models were used to dock over 150,000 molecules in silico (or virtually) to the structure of the receptor with the Internal Coordinates Mechanics (ICM) program. Thirty ligand candidates were tested in vitro.
CONCLUSIONS
Two novel agonists resulting from the predicted receptor model were active at 50 nM. One of them displays novel structural features which may translate into the development of new ligands for cancer therapy.
背景
几种视黄酸受体（RAR）激动剂对多种癌症类型具有治疗活性；然而，不可接受的毒性特征阻碍了药物的开发。因此，呈现新颖结构和化学特征的RAR激动剂可能为发现针对乳腺癌、肺癌、前列腺癌或白血病的先导化合物开辟新途径。
结果
我们分析了已知配体结合后活性位点残基的诱导契合。使用推导的结合位点模型，通过内部坐标力学（ICM）程序在计算机上（或虚拟地）将超过150,000个分子对接至受体结构。在体外测试了30种配体候选物。
结论
由预测的受体模型产生的两种新型激动剂在50 nM时具有活性。其中一种具有新颖的结构特征，这可能转化为开发用于癌症治疗的新配体。
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