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000891037 1001_ $$0P:(DE-Juel1)172836$$aGossen, Jonas$$b0
000891037 245__ $$aA Blueprint for High Affinity SARS-CoV-2 Mpro Inhibitors from Activity-Based Compound Library Screening Guided by Analysis of Protein Dynamics
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000891037 520__ $$aThe SARS-CoV-2 coronavirus outbreak continues to spread at a rapid rate worldwide. The main protease (Mpro) is an attractive target for anti-COVID-19 agents. Unexpected difficulties have been encountered in the design of specific inhibitors. Here, by analyzing an ensemble of ∼30 000 SARS-CoV-2 Mpro conformations from crystallographic studies and molecular simulations, we show that small structural variations in the binding site dramatically impact ligand binding properties. Hence, traditional druggability indices fail to adequately discriminate between highly and poorly druggable conformations of the binding site. By performing ∼200 virtual screenings of compound libraries on selected protein structures, we redefine the protein’s druggability as the consensus chemical space arising from the multiple conformations of the binding site formed upon ligand binding. This procedure revealed a unique SARS-CoV-2 Mpro blueprint that led to a definition of a specific structure-based pharmacophore. The latter explains the poor transferability of potent SARS-CoV Mpro inhibitors to SARS-CoV-2 Mpro, despite the identical sequences of the active sites. Importantly, application of the pharmacophore predicted novel high affinity inhibitors of SARS-CoV-2 Mpro, that were validated by in vitro assays performed here and by a newly solved X-ray crystal structure. These results provide a strong basis for effective rational drug design campaigns against SARS-CoV-2 Mpro and a new computational approach to screen protein targets with malleable binding sites.
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000891037 7001_ $$0P:(DE-Juel1)181061$$aAlbani, Simone$$b1
000891037 7001_ $$0P:(DE-HGF)0$$aHanke, Anton$$b2
000891037 7001_ $$0P:(DE-Juel1)179040$$aJoseph, Benjamin P.$$b3
000891037 7001_ $$0P:(DE-HGF)0$$aBergh, Cathrine$$b4
000891037 7001_ $$0P:(DE-HGF)0$$aKuzikov, Maria$$b5
000891037 7001_ $$0P:(DE-HGF)0$$aCostanzi, Elisa$$b6
000891037 7001_ $$0P:(DE-HGF)0$$aManelfi, Candida$$b7
000891037 7001_ $$0P:(DE-HGF)0$$aStorici, Paola$$b8
000891037 7001_ $$0P:(DE-HGF)0$$aGribbon, Philip$$b9
000891037 7001_ $$0P:(DE-HGF)0$$aBeccari, Andrea R.$$b10
000891037 7001_ $$0P:(DE-HGF)0$$aTalarico, Carmine$$b11
000891037 7001_ $$0P:(DE-HGF)0$$aSpyrakis, Francesca$$b12
000891037 7001_ $$0P:(DE-HGF)0$$aLindahl, Erik$$b13
000891037 7001_ $$0P:(DE-HGF)0$$aZaliani, Andrea$$b14
000891037 7001_ $$0P:(DE-Juel1)145614$$aCarloni, Paolo$$b15
000891037 7001_ $$0P:(DE-HGF)0$$aWade, Rebecca C.$$b16
000891037 7001_ $$0P:(DE-HGF)0$$aMusiani, Francesco$$b17
000891037 7001_ $$0P:(DE-HGF)0$$aKokh, Daria B.$$b18
000891037 7001_ $$0P:(DE-Juel1)145921$$aRossetti, Giulia$$b19$$eCorresponding author
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