Abstract
Protein kinases constitute an attractive family of enzyme targets with high relevance to cell and disease biology. Small molecule inhibitors are powerful tools to dissect and elucidate the function of kinases in chemical biology research and to serve as potential starting points for drug discovery. However, the discovery and development of novel inhibitors remains challenging. Here, we describe a structure-based de novo design approach that generates novel, hinge-binding fragments that are synthetically feasible and can be elaborated to small molecule libraries. Starting from commercially available compounds, core fragments were extracted, filtered for pharmacophoric properties compatible with hinge-region binding, and docked into a panel of protein kinases. Fragments with a high consensus score were subsequently short-listed for synthesis. Application of this strategy led to a number of core fragments with no previously reported activity against kinases. Small libraries around the core fragments were synthesized, and representative compounds were tested against a large panel of protein kinases and subjected to co-crystallization experiments. Each of the tested compounds was active against at least one kinase, but not all kinases in the panel were inhibited. A number of compounds showed high ligand efficiencies for therapeutically relevant kinases; among them were MAPKAP-K3, SRPK1, SGK1, TAK1, and GCK for which only few inhibitors are reported in the literature.
Highlights
A wealth of structural information has revealed the general architecture of protein kinases, their binding sites, and complex regulation.[4,5] The ATP-binding sites of most protein kinases share similar features (Figure 1a).[6,7] A key recognition motive is the hinge region that forms hydrogen bonds to the adenine moiety of ATP and is targeted by many kinase inhibitors
Small libraries around the core fragments were synthesized, and representative compounds were tested against a large panel of protein kinases and subjected to co-crystallization experiments
We report on the structure-based de novo design of protein kinase inhibitors
Summary
We report on the structure-based de novo design of protein kinase inhibitors. The approach is centered on fragments that have precedence for synthesis but are not commercially available with the required substitution pattern. An in silico screening cascade was established for the design of novel kinase inhibitor libraries (Figure 1b) This approach consisted of the following four principle steps: core fragment extraction out of commercially available compounds, selection of candidate core fragments, docking of core fragments, and fragment expansion. About 6,000 core fragments that passed this filter step were docked into the binding sites of a panel of 46 different protein kinases (Supplementary Table S1). The kinases presented in the kinase panel were not inhibited by the 15 compounds selected to present the different core fragments (Figure 5b, Supplementary Tables S3 and S4).
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