Non-hinge-binding pyrazolo[1,5-a]pyrimidines as potent B-Raf kinase inhibitors

Berger, Dan M.; Torres, Nancy; Dutia, Minu; Powell, Dennis; Ciszewski, Gregory; Gopalsamy, Ariamala; Levin, Jeremy I.; Kim, Kyung‐Hee; Xu, Weixin; Wilhelm, James E.; Hu, Yongbo; Collins, Karen; Feldberg, Larry; Kim, Steven; Frommer, Eileen; Wojciechowicz, Donald; Mallon, Robert

doi:10.1016/j.bmcl.2009.10.049

Cited by 33 publications

(13 citation statements)

References 5 publications

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“…Thirty type II inhibitors [34] of Braf (3II5), 14 charged inhibitors [33] of p38 alpha and another 20 p38 alpha inhibitors [35] (1YWR) are used as the test set. Protein structures were taken from the X-ray structure (PDB code indicated in the brackets) and prepared as described below.…”

Section: Methodsmentioning

confidence: 99%

Hydrogen Bonding Penalty upon Ligand Binding

Zhao

Huang

2011

PLoS ONE

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Ligand binding involves breakage of hydrogen bonds with water molecules and formation of new hydrogen bonds between protein and ligand. In this work, the change of hydrogen bonding energy in the binding process, namely hydrogen bonding penalty, is evaluated with a new method. The hydrogen bonding penalty can not only be used to filter unrealistic poses in docking, but also improve the accuracy of binding energy calculation. A new model integrated with hydrogen bonding penalty for free energy calculation gives a root mean square error of 0.7 kcal/mol on 74 inhibitors in the training set and of 1.1 kcal/mol on 64 inhibitors in the test set. Moreover, an application of hydrogen bonding penalty into a high throughput docking campaign for EphB4 inhibitors is presented, and remarkably, three novel scaffolds are discovered out of seven tested. The binding affinity and ligand efficiency of the most potent compound is about 300 nM and 0.35 kcal/mol per non-hydrogen atom, respectively.

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Section: Methodsmentioning

confidence: 99%

Hydrogen Bonding Penalty upon Ligand Binding

Zhao

Huang

2011

PLoS ONE

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“…Additionally, the Type II inhibitors characteristically hydrogen bond to Asp381 and Glu286. We note that the distinct a/h orientation is witnessed in the most recently solved Type II/ kinase crystals structures; for example new structures not included in our data set involve ligand complexes with c-Src [48], p38 MAP kinase [49] and B-Raf [50]; in these structures, the ligands adopt an angle a of 73°, 62°and 81°r espectively, as well as forming good hydrogen bonds with Asp381 and Glu286 (Table 9S). Caution should be exercised, however, as exceptions to this shape can be found: for example, the bound pose of Type II compound BIRB796 in pyk2 has an a value is 46° [51].…”

Section: Discussionmentioning

confidence: 89%

Application of shape-based and pharmacophore-based in silico screens for identification of Type II protein kinase inhibitors

Mucs

Bryce

Bonnet

2011

J Comput Aided Mol Des

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The identification of new, potent and selective inhibitors of important protein kinase targets is a major goal of drug discovery. Here we analyze the crystal structures of 55 protein kinase complexes with Type II inhibitors and find they adopt a conserved twisted V-shape, with an angle of 121 ± 8° and twist of 78 ± 8°. The tightly conserved twist appears important in ensuring ligands curve around the protein backbone and towards the deep pocket. From this, we develop predictive pharmacophore- and shape-based screens to identify Type II inhibitors from a database which also contains Type I inhibitors as decoys. Both approaches exhibit a good level of discrimination for Type II molecules. The most effective pharmacophore model requires six features and three excluded volume regions. Shape-based screening using ROCS generally performs at least as well as pharmacophore approaches. There is only a moderate dependence of shape-based or pharmacophore-based screens on the underlying conformer generator (MOE, Macromodel, Omega and SPE), as well as on ligand linkage chemistry (amide and urea). Finally, we apply our approach to retrieval of Type II inhibitors from a modified version of the DUD database, containing over 104,000 compounds. We observe good enrichment, providing further evidence that the in silico screens developed here will constitute useful guides for identification of small molecule inhibitors targetting protein kinases in their inactive conformational state.

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“…The 4-Ph-CH 2 -NH(CH 3 ) 2 + group of 3II5 is placed in a region of the cavity unoccupied by 3IDP, thus increasing the contribution of V471, L597, E600 and S465 ( Figure S4, Supporting Information). Moreover, the presence of a positively charged group in this region of the binding site favors the formation of a hydrogen bond with the carbonyl oxygen of I463, which has not been observed in the crystallographic structure [36]. However, by comparison with 3IDP, the orientation adopted by this 4-Ph-CH 2 -NH(CH 3 ) 2 + group in 3II5 implies a drop in the contribution of residues A481, W531 and C532 to the stability of the 3II5 complex.…”

Section: Pairwise Binding Free Energy Decompositionmentioning

confidence: 99%

“…The atomic coordinates of the five complexes with V600E B-Raf were retrieved from the Protein Data Bank (PDB entries: 1UWJ [3], 3C4C [34], 3IDP [35], 3II5 [36], 3Q96 [237]). In the case of the 1UWJ and 3Q96 complexes, only one of the two asymmetrically packed kinase-inhibitor complexes of the crystallographic unit was selected for further studies.…”

Section: Preparation Of the Complexesmentioning

confidence: 99%