Abstract
Protein kinases have been found to possess two characteristic conformations in their activation-loops: the active DFG-in conformation and the inactive DFG-out conformation. Recently, it has been very interesting to develop type-II inhibitors which target the DFG-out conformation and are more specific than the type-I inhibitors binding to the active DFG-in conformation. However, solving crystal structures of kinases with the DFG-out conformation remains a challenge, and this seriously hampers the application of the structure-based approaches in development of novel type-II inhibitors. To overcome this limitation, here we present a computational approach for predicting the DFG-out inactive conformation using the DFG-in active structures, and develop related conformational selection protocols for the uses of the predicted DFG-out models in the binding pose prediction and virtual screening of type-II ligands. With the DFG-out models, we predicted the binding poses for known type-II inhibitors, and the results were found in good agreement with the X-ray crystal structures. We also tested the abilities of the DFG-out models to recognize their specific type-II inhibitors by screening a database of small molecules. The AUC (area under curve) results indicated that the predicted DFG-out models were selective toward their specific type-II inhibitors. Therefore, the computational approach and protocols presented in this study are very promising for the structure-based design and screening of novel type-II kinase inhibitors.
Highlights
Human genome contains about 518 genes which encode protein kinases (PKs) and account for approximately 2% of the whole human genes [1]
The catalytic domain of a PK consists of a smaller N-terminal lobe (N-lobe) and a bigger C-terminal lobe (Clobe) [8]
Results showed that the predicted DFG-out models were selective toward their specific type-II inhibitors. All these results suggested that the presented computational approach would have practical applications in the structure-based design and screening of novel type-II kinase inhibitors
Summary
Human genome contains about 518 genes which encode protein kinases (PKs) and account for approximately 2% of the whole human genes [1] This large protein family is responsible for regulating nearly every aspect of the cellular activities through protein phosphorylation. The PK catalytic domains are one of the most common domains in which mutations may lead to human cancers For such reasons, protein kinases have long been regarded as one of the most important families of drug targets [4,5,6]. The phenylalanine (Phe) side-chain occupies the ATP-binding pocket, and the aspartate (Asp) side-chain is located in the outside of the pocket (DFG-in conformation). Some human kinases were shown to be able to adopt the DFG-out conformation [12,13,14], and it was suggested that the DFG-in and DFG-out conformations might co-exist in the way of dynamic equilibrium [10]
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