Quantum Chemical-Based Protocol for the Rational Design of Covalent Inhibitors
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- 作者：Tanja Schirmeister ; Jochen Kesselring ; Sascha Jung ; Thomas H. Schneider ; Anastasia Weickert ; Johannes Becker ; Wook Lee ; Denise Bamberger ; Peter R. Wich ; Ute Distler ; Stefan Tenzer ; Patrick Johé ; Ute A. Hellmich ; Bernd Engels
- 刊名：Journal of the American Chemical Society
- 出版年：2016
- 出版时间：July 13, 2016
- 年：2016
- 卷：138
- 期：27
- 页码：8332-8335
- 全文大小：318K
- 年卷期：0
- ISSN：1520-5126
文摘
We propose a structure-based protocol for the development of customized covalent inhibitors. Starting from a known inhibitor, in the first and second steps appropriate substituents of the warhead are selected on the basis of quantum mechanical (QM) computations and hybrid approaches combining QM with molecular mechanics (QM/MM). In the third step the recognition unit is optimized using docking approaches for the noncovalent complex. These predictions are finally verified by QM/MM or molecular dynamic simulations. The applicability of our approach is successfully demonstrated by the design of reversible covalent vinylsulfone-based inhibitors for rhodesain. The examples show that our approach is sufficiently accurate to identify compounds with the desired properties but also to exclude nonpromising ones.