Novel p38α MAP kinase inhibitors identified from yoctoReactor DNA-encoded small molecule library
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Novel p38α MAP kinase inhibitors identified from yoctoReactor DNA-encoded small molecule library. / Petersen, L. K.; Blakskjær, P.; Chaikuad, A.; Christensen, A. B.; Dietvorst, J.; Holmkvist, J.; Knapp, S.; Kořínek, M.; Larsen, L. K.; Pedersen, A. E.; Röhm, S.; Sløk, F. A.; Hansen, N. J V.
I: MedChemComm, Bind 7, 2016, s. 1332-1339.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Novel p38α MAP kinase inhibitors identified from yoctoReactor DNA-encoded small molecule library
AU - Petersen, L. K.
AU - Blakskjær, P.
AU - Chaikuad, A.
AU - Christensen, A. B.
AU - Dietvorst, J.
AU - Holmkvist, J.
AU - Knapp, S.
AU - Kořínek, M.
AU - Larsen, L. K.
AU - Pedersen, A. E.
AU - Röhm, S.
AU - Sløk, F. A.
AU - Hansen, N. J V
PY - 2016
Y1 - 2016
N2 - A highly specific and potent (7 nM cellular IC50) inhibitor of p38α kinase was identified directly from a 12.6 million membered DNA-encoded small molecule library. This was achieved using the high fidelity yoctoReactor technology (yR) for preparing the DNA-encoded library, and a homogeneous screening technique-the binder trap enrichment technology (BTE). Although structurally atypical to other kinase blockers, this inhibitor was found by X-ray crystallography to interact with the ATP binding site and provide strong distortion of the P-loop. Remarkably, it assumed an alternative binding mode as it lacks key features of known kinase inhibitors such as typical hinge binding motifs. Interestingly, the inhibitor bound assuming a canonical type-II ('DFG-out') binding mode by forming hinge hydrogen bonds with the backbone, showed excellent shape complementarity, and formed a number of specific polar interactions. Moreover, the crystal structure showed, that although buried in the p38α active site, the original DNA attachment point of the compound was accessible through a channel created by the distorted P-loop conformation. This study demonstrates the usability of DNA-encoded library technologies for identifying novel chemical matter with alternative binding modes to provide a good starting point for drug development.
AB - A highly specific and potent (7 nM cellular IC50) inhibitor of p38α kinase was identified directly from a 12.6 million membered DNA-encoded small molecule library. This was achieved using the high fidelity yoctoReactor technology (yR) for preparing the DNA-encoded library, and a homogeneous screening technique-the binder trap enrichment technology (BTE). Although structurally atypical to other kinase blockers, this inhibitor was found by X-ray crystallography to interact with the ATP binding site and provide strong distortion of the P-loop. Remarkably, it assumed an alternative binding mode as it lacks key features of known kinase inhibitors such as typical hinge binding motifs. Interestingly, the inhibitor bound assuming a canonical type-II ('DFG-out') binding mode by forming hinge hydrogen bonds with the backbone, showed excellent shape complementarity, and formed a number of specific polar interactions. Moreover, the crystal structure showed, that although buried in the p38α active site, the original DNA attachment point of the compound was accessible through a channel created by the distorted P-loop conformation. This study demonstrates the usability of DNA-encoded library technologies for identifying novel chemical matter with alternative binding modes to provide a good starting point for drug development.
U2 - 10.1039/c6md00241b
DO - 10.1039/c6md00241b
M3 - Journal article
AN - SCOPUS:84978909845
VL - 7
SP - 1332
EP - 1339
JO - MedChemComm
JF - MedChemComm
SN - 2040-2503
ER -
ID: 168856168