Abstract
Many drugs are promiscuous and bind to multiple targets. On the one hand, these targets may be linked to unwanted side effects, but on the other, they may achieve a combined desired effect (polypharmacology) or represent multiple diseases (drug repositioning). With the growth of 3D structures of drug-target complexes, it is today possible to study drug promiscuity at the structural level and to screen vast amounts of drug-target interactions to predict side effects, polypharmacological potential, and repositioning opportunities. Here, we pursue such an approach to identify drugs inactivating B-cells, whose dysregulation can function as a driver of autoimmune diseases. Screening over 500 kinases, we identified 22 candidate targets, whose knock out impeded the activation of B-cells. Among these 22 is the gene KDR, whose gene product VEGFR2 is a prominent cancer target with anti-VEGFR2 drugs on the market for over a decade. The main result of this paper is that structure-based drug repositioning for the identified kinase targets identified the cancer drug ibrutinib as micromolar VEGFR2 inhibitor with a very high therapeutic index in B-cell inactivation. These findings prove that ibrutinib is not only acting on the Bruton’s tyrosine kinase BTK, against which it was designed. Instead, it may be a polypharmacological drug, which additionally targets angiogenesis via inhibition of VEGFR2. Therefore ibrutinib carries potential to treat other VEGFR2 associated disease. Structure-based drug repositioning explains ibrutinib’s anti VEGFR2 action through the conservation of a specific pattern of interactions of the drug with BTK and VEGFR2. Overall, structure-based drug repositioning was able to predict these findings at a fraction of the time and cost of a conventional screen.
Highlights
The number of ways a drug can interact with its target is limited
We found 22 candidate targets, whose silencing potentially inactivates B-cells
Many of these candidate targets are already drug targets with approved drugs, which will be beneficial for future drug repositioning efforts
Summary
The number of ways a drug can interact with its target is limited. While the exact number may be debatable, a limit itself has important consequences: there is redundancy and re-use in drug-target interaction, which makes it difficult to design a targetspecific or one target-only drug. Drug promiscuity, a drug hitting multiple targets, is rather the normality than the exception [3,4,5]. In order to test the efficacy and selectivity of the hit compounds on B-cells, 4 assays were performed: B-cell assay, Mixed Lymphocyte Reaction (MLR), WST-1 assay on RPMI1788 cells (B-cell line) and cytotoxicity WST-1 assay on Jurkat cells (T-cell line). The human B cell line RPMI1788 (American Type Culture Collection, USA) and the human T cell line Jurkat (European Collection of Cell Cultures, ECACC, England) were maintained in RPMI1640 culture medium (BioWhittaker, Lonza, Verviers, Belgium) containing 10% foetal calf serum (FCS, HyClone Thermo Scientific, United Kingdom) and 5 μg/mL gentamicin sulphate (BioWhittaker, Lonza, Verviers, Belgium) at 37 ̊C and 5% CO2
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