Magnet for the Needle in Haystack: “Crystal Structure First” Fragment Hits Unlock Active Chemical Matter Using Targeted Exploration of Vast Chemical Spaces
- Janis Müller
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- Raphael Klein
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- Olga TarkhanovaOlga TarkhanovaChemspace LLC, 85 Chervonotkatska Street, Suite 1, 03190Kyïv, UkraineMore by Olga Tarkhanova
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- Anastasiia GryniukovaAnastasiia GryniukovaEnamine Ltd., 78 Chervonotkatska Street 78, 02094Kyïv, UkraineMore by Anastasiia Gryniukova
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- Petro Borysko
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- Stefan Merkl
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- Moritz Ruf
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- Alexander NeumannAlexander NeumannBioSolveIT GmbH, An der Ziegelei 79, 53757Sankt Augustin, GermanyMore by Alexander Neumann
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- Marcus GastreichMarcus GastreichBioSolveIT GmbH, An der Ziegelei 79, 53757Sankt Augustin, GermanyMore by Marcus Gastreich
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- Yurii S. MorozYurii S. MorozChemspace LLC, 85 Chervonotkatska Street, Suite 1, 03190Kyïv, UkraineTaras Shevchenko National University of Kyïv, 60 Volodymyrska Street 60, Kyïv01601, UkraineMore by Yurii S. Moroz
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- Gerhard KlebeGerhard KlebeDepartment for Pharmaceutical Chemistry, Philipps-University Marburg, Marbacher Weg 6, 35037Marburg, GermanyMore by Gerhard Klebe
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- Serghei Glinca*Serghei Glinca*Email: [email protected] Tel.: +49 6421 968814-0.CrystalsFirst GmbH, Marbacher Weg 6, 35037Marburg, GermanyMore by Serghei Glinca
Abstract
Fragment-based drug discovery (FBDD) has successfully led to approved therapeutics for challenging and “undruggable” targets. In the context of FBDD, we introduce a novel, multidisciplinary method to identify active molecules from purchasable chemical space. Starting from four small-molecule fragment complexes of protein kinase A (PKA), a template-based docking screen using Enamine’s multibillion REAL Space was performed. A total of 93 molecules out of 106 selected compounds were successfully synthesized. Forty compounds were active in at least one validation assay with the most active follow-up having a 13,500-fold gain in affinity. Crystal structures for six of the most promising binders were rapidly obtained, verifying the binding mode. The overall success rate for this novel fragment-to-hit approach was 40%, accomplished in only 9 weeks. The results challenge the established fragment prescreening paradigm since the standard industrial filters for fragment hit identification in a thermal shift assay would have missed the initial fragments.
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