Automated Docking with Protein Flexibility in the Design of Femtomolar "Click Chemistry" Inhibitors of Acetylcholinesterase

作者：Morris Garrett M; Green Luke G; Radic Zoran; Taylor Palmer; Sharpless K Barry; Olson Arthur J; Grynszpan Flavio^*

来源：Journal of Chemical Information and Modeling, 2013, 53(4): 898-906.

DOI：10.1021/ci300545a

The use of computer-aided structure-based drug design prior to synthesis has proven to be generally valuable in suggesting improved binding analogues of existing ligands.(1) Here we describe the application of the program AutoDock(2) to the design of a focused library that was used in the "click chemistry in-situ" generation of the most potent noncovalent inhibitor of the native enzyme acetylcholinesterase (AChE) yet developed (K-d = similar to 100 fM).(3) AutoDock version 3.0.5 has been widely distributed and successfully used to predict bound conformations of flexible ligands. Here, we also used a version of AutoDock which permits additional conformational flexibility in selected amino acid side chains of the target protein.

• 出版日期2013-4