title: Computational and experimental prediction of human C-type lectin receptor druggability.
abstract: Mammalian C-type lectin receptors (CTLRS) are involved in many aspects of immune cell regulation such as pathogen recognition, clearance of apoptotic bodies, and lymphocyte homing. Despite a great interest in modulating CTLR recognition of carbohydrates, the number of specific molecular probes is limited. To this end, we predicted the druggability of a panel of 22 CTLRs using DoGSiteScorer. The computed druggability scores of most structures were low, characterizing this family as either challenging or even undruggable. To further explore these findings, we employed a fluorine-based nuclear magnetic resonance screening of fragment mixtures against DC-SIGN, a receptor of pharmacological interest. To our surprise, we found many fragment hits associated with the carbohydrate recognition site (hit rate = 13.5%). A surface plasmon resonance-based follow-up assay confirmed 18 of these fragments (47%) and equilibrium dissociation constants were determined. Encouraged by these findings we expanded our experimental druggability prediction to Langerin and MCL and found medium to high hit rates as well, being 15.7 and 10.0%, respectively. Our results highlight limitations of current in silico approaches to druggability assessment, in particular, with regard to carbohydrate-binding proteins. In sum, our data indicate that small molecule ligands for a larger panel of CTLRs can be developed.
authors: Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces , Potsdam , Germany ; Department of Biology, Chemistry, and Pharmacy, Freie Universität Berlin , Berlin , Germany.
authors: Jonas
authors: J
authors: Aretz
authors: Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces , Potsdam , Germany ; Department of Biology, Chemistry, and Pharmacy, Freie Universität Berlin , Berlin , Germany.
authors: Eike-Christian
authors: EC
authors: Wamhoff
authors: Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces , Potsdam , Germany ; Department of Biology, Chemistry, and Pharmacy, Freie Universität Berlin , Berlin , Germany.
authors: Jonas
authors: J
authors: Hanske
authors: Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces , Potsdam , Germany.
authors: Dario
authors: D
authors: Heymann
authors: Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces , Potsdam , Germany ; Department of Biology, Chemistry, and Pharmacy, Freie Universität Berlin , Berlin , Germany.
authors: Christoph
authors: C
authors: Rademacher
keywords: C-type lectin receptors; DC-SIGN; MCL; NMR screening; druggability; fragment screening; inhibitor; langerin