Towards in silico lead optimization: scores from ensembles of protein/ligand conformations reliably correlate with biological activity.
Towards in silico lead optimization: scores from ensembles of protein/ligand conformations reliably correlate with biological activity.
复制标题
迈向计算机先导化合物优化：蛋白质/配体构象整体的得分与生物活性可靠地相关。
DOI：
10.1002/prot.21201
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发表时间：
2007
期刊：
影响因子：
2.9
通讯作者：
Anderson,AmyC
中科院分区：
文献类型：
--
作者：
Popov,VeljkoM;Yee,WAtom;Anderson,AmyC
Accurately ranking protein/ligand interactions and distinguishing subtle differences between homologous compounds in a virtual focused libraryin silicois essential in a structure‐based drug discovery program. In order to establish a predictive model to design novel inhibitors of dihydrofolate reductase (DHFR) from the parasitic protozoa,Cryptosporidium hominis, we docked a series of 30 DHFR inhibitors with measured inhibition constants against the crystal structure of the protein. By including protein flexibility and averaging the energies of the 25 lowest protein/ligand conformers we obtained more accurate total nonbonded energies from which we calculated a predicted biological activity. The calculated and measured biological activities showed reliable correlations of 72.9%. Additionally, visual analysis of the ensemble of protein/ligand conformations revealed alternative ligand binding pockets in the active site. Using the same principles we then created a homology model of DHFR fromToxoplasma gondiiand docked 11 inhibitors. A correlation of 50.2% between docking score and activity validates both the method and the model. The correlations presented here are particularly compelling considering the high structural similarity of the ligands and the fact that we have used structures derived from crystallographic data and homology modeling. These docking principles may be useful in any lead optimization study where accurate ranking of similar compounds is desired. Proteins 2007. © 2006 Wiley‐Liss, Inc.
