Ansaris, Four Valley Square, 512 Township Line Rd, Blue Bell, Pennsylvania 19422, United States.
J Chem Inf Model. 2011 Jan 24;51(1):52-60. doi: 10.1021/ci100256u. Epub 2010 Nov 30.
We introduce TICRA (transplant-insert-constrain-relax-assemble), a method for modeling the structure of unknown protein-ligand complexes using the X-ray crystal structures of homologous proteins and ligands with known activity. We present results from modeling the structures of protein kinase-inhibitor complexes using p38 and Lck as examples. These examples show that the TICRA method may be used prospectively to create and refine models for protein kinase-inhibitor complexes with an overall backbone rmsd of less than 0.75 Å for the kinase domain, when compared to published X-ray crystal structures. Further refinement of the models of the kinase domains of p38 and Lck in complex with their cognate ligands from the published crystal structures was able to improve the rmsd's of the model complexes to below 0.5 Å. Our results show that TICRA is a useful approach to the problem of structure-based drug design in cases where little structural information is available for the target proteins and the binding mode of active compounds is unknown.
我们介绍了 TICRA（移植-插入-约束-松弛-组装）方法，该方法使用具有已知活性的同源蛋白质和配体的 X 射线晶体结构来模拟未知蛋白质-配体复合物的结构。我们以 p38 和 Lck 为例，展示了使用 TICRA 方法对蛋白激酶抑制剂复合物结构进行建模的结果。这些例子表明，当与已发表的 X 射线晶体结构相比时，TICRA 方法可以前瞻性地用于创建和改进蛋白激酶抑制剂复合物的模型，使激酶结构域的整体骨架 rmsd 小于 0.75 Å。进一步细化 p38 和 Lck 激酶结构域与它们同源配体的模型，使其与已发表晶体结构中的模型复合物的 rmsd 降低至 0.5 Å 以下。我们的结果表明，在缺乏目标蛋白结构信息且活性化合物的结合模式未知的情况下，TICRA 是一种用于基于结构药物设计问题的有用方法。
