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J Am Chem Soc. 2016 Jul 13;138(27):8332-5. doi: 10.1021/jacs.6b03052. Epub 2016 Jul 1.

Quantum Chemical-Based Protocol for the Rational Design of Covalent Inhibitors.

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Institut für Pharmazie und Biochemie, Johannes Gutenberg Universität Mainz , Staudinger Weg 5, 55128 Mainz, Germany.
Institut für Phys. und Theor. Chemie, Universität Würzburg , Emil-Fischer-Straße 42, 97074 Würzburg, Germany.
Institut für Immunologie, Universitätsmedizin der Johannes-Gutenberg Universität Mainz , Langenbeckstr. 1, 55131 Mainz, Germany.
Institut für Pharmazie und Biochemie, Johannes Gutenberg Universität Mainz , J.-J. Becherweg 30, 55128 Mainz, Germany.
Center for Biomolecular Magnetic Resonance (BMRZ), Goethe University , Theodor-W.-Adorno-Platz 1, 60323 Frankfurt, Germany.


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.


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