The design, synthesis, and evaluation of 8 hybrid DFG-out allosteric kinase inhibitors: A structural analysis of the binding interactions of Gleevec®, Nexavar®, and BIRB-796

Dietrich, Justin; Hulme, Christopher; Hurley, Laurence H.

doi:10.1016/j.bmc.2010.05.063

Cited by 156 publications

(129 citation statements)

References 35 publications

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“…We observe the standard H bonding between the urea linker of the SKR compounds with CDK8/CycC as reported for DFG-out binders such as BIRB796 (12,13,25,31), but only further H bonding with the hinge region triggers a detectable residence time. This is consistent with literature reporting that solvent-shielded H bonding slows down dissociation (32).…”

Section: Discussionsupporting

confidence: 77%

“…The recent clinical success of the small molecule inhibitors sorafenib (BAY-43006, Bayer Pharma) and imatinib (STI-571, Novartis Pharma AG) has been attributed to their deep pocket binding mode (12). The "deep pocket" (13) is adjacent to the kinase ATP binding site and accessible in protein kinases by the rearrangement of the DFG motif (a short motif composed of the residues AspPhe-Gly near the N-terminal region of the activation loop) from the active (DFG-in) to the inactive state (DFG-out) (13,14).…”

mentioning

confidence: 99%

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Structure–kinetic relationship study of CDK8/CycC specific compounds

Schneider

Böttcher²,

Huber

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

120

136

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In contrast with the very well explored concept of structure-activity relationship, similar studies are missing for the dependency between binding kinetics and compound structure of a protein ligand complex, the structure-kinetic relationship. Here, we present a structure-kinetic relationship study of the cyclin-dependent kinase 8 (CDK8)/cyclin C (CycC) complex. The scaffold moiety of the compounds is anchored in the kinase deep pocket and extended with diverse functional groups toward the hinge region and the front pocket. These variations can cause the compounds to change from fast to slow binding kinetics, resulting in an improved residence time. The flip of the DFG motif ("DMG" in CDK8) to the inactive DFG-out conformation appears to have relatively little influence on the velocity of binding. Hydrogen bonding with the kinase hinge region contributes to the residence time but has less impact than hydrophobic complementarities within the kinase front pocket.kinetic profiling | structure-based drug design T he cyclin-dependent kinase 8/cyclin C (CDK8/CycC) complex is a potent oncogene (1-4), involved in transcription and regulation of transcriptional activity (5-10), linked to epigenetic processes (11), and regarded as an attractive drug target. The recent clinical success of the small molecule inhibitors sorafenib (BAY-43006, Bayer Pharma) and imatinib (STI-571, Novartis Pharma AG) has been attributed to their deep pocket binding mode (12). The "deep pocket" (13) is adjacent to the kinase ATP binding site and accessible in protein kinases by the rearrangement of the DFG motif (a short motif composed of the residues AspPhe-Gly near the N-terminal region of the activation loop) from the active (DFG-in) to the inactive state (DFG-out) (13,14). Binding of a type II compound to such a DFG-out conformation often includes slow binding kinetics (15) with a prolonged "residence time," which is defined as the period for which a target is occupied by a compound (16). Residence time is currently considered to be a key success factor for compound optimization during drug discovery and perhaps as important as the apparent affinity such as half-inhibitory concentration (IC 50 ) or dissociation constant (K d ) (16,17). Accordingly, residence time could be a key to providing enhanced potency in vivo (18) and a means to improve the correlation of in vitro and in vivo efficacy of drugs (19). Despite the increased acceptance of the need to understand binding kinetics, the interplay between compound-target interactions and binding kinetics is in general too complex and poorly understood to enable prediction of the essential dynamic properties. The impact of the combination of kinetic data of proteininhibitor interactions with crystallographic studies has been recognized with pioneer studies such as bovine trypsin in complex with the bovine pancreatic trypsin inhibitor (20). The concept of structure-activity relationships describing the interdependency between binding affinity and compound structure has been well explored in the l...

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Section: Discussionsupporting

confidence: 77%

mentioning

confidence: 99%

Structure–kinetic relationship study of CDK8/CycC specific compounds

Schneider

Böttcher²,

Huber

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

120

136

View full text Add to dashboard Cite

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“…This class, known as type II inhibitors, appear to display much higher selectivity. The DFG-out conformation has thus attracted significant interest in the discovery and development of selective kinase inhibitors in the past few years [8][9][10][11][12][13][14]. However, a recent analysis of binding modes of type II inhibitors indicates that there may be less selectivity than initially believed [15].…”

Section: Introductionmentioning

confidence: 98%

Characterization of interactions and pharmacophore development for DFG-out inhibitors to RET tyrosine kinase

2015

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RET (rearranged during transfection) tyrosine kinase is a promising target for several human cancers. Abt-348, Birb-796, Motesanib and Sorafenib are DFG-out multi-kinase inhibitors that have been reported to inhibit RET activity with good IC50 values. Although the DFG-out conformation has attracted great interest in the design of type II inhibitors, the structural requirements for binding to the RET DFG-out conformation remains unclear. Herein, the DFG-out conformation of RET was determined by homology modelling, the four inhibitors were docked, and the binding modes investigated by molecular dynamics simulation. Binding free energies were calculated using the molecular mechanics/Poisson-Bolzmann surface area (MM/PBSA) method. The trends in predicted binding free affinities correlated well with experimental data and were used to explain the activity difference of the studied inhibitors. Per-residue energy decomposition analyses provided further information on specific interaction properties. Finally, we also conducted a detailed e-pharmacophore modelling of the different RET-inhibitor complexes, explaining the common and specific pharmacophore features of the different complexes. The results reported herein will be useful in future rational design of novel DFG-out RET inhibitors.

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“…Many research groups performed studies on the DFG-out conformation of kinases and developed type-II kinase inhibitors. [7][8][9][10][11][12][13][14][15][16][17] Previous reports indicated that allosteric binding pocket of p38 was used to find out potent molecules. This lead to discovery of potent allosteric inhibitor BIRB, currently in phase II clinical trials.…”

Section: Introductionmentioning

confidence: 99%

Theoretical Characterization of Binding Mode of Organosilicon Inhibitor with p38: Docking, MD Simulation and MM/GBSA Free Energy Approach

Gadhe¹,

Balupuri²,

Kothandan³

et al. 2014

Bulletin of the Korean Chemical Society

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P38 mitogen activated protein (MAP) kinase is an important anti-inflammatory drug target, which can be activated by responding to various stimuli such as stress and immune response. Based on the conformation of the conserved DFG loop (in or out), binding inhibitors are termed as type-I and II. Type-I inhibitors are ATP competitive, whereas type-II inhibitors bind in DFG-out conformation of allosteric pocket. It remains unclear that how these allosteric inhibitors stabilize the DFG-out conformation and interact. Organosilicon compounds provide unusual opportunity to enhance potency and diversity of drug molecules due to their low toxicity. However, very few examples have been reported to utilize this property. In this regard, we performed docking of an inhibitor (BIRB) and its silicon analog (Si-BIRB) in an allosteric binding pocket of p38. Further, molecular dynamics (MD) simulations were performed to study the dynamic behavior of the simulated complexes. The difference in the biological activity and mechanism of action of the simulated inhibitors could be explained based on the molecular mechanics/generalized Born surface area (MM/GBSA) binding free energy per residue decomposition. MM/GBSA showed that biological activities were related with calculated binding free energy of inhibitors. Analyses of the per-residue decomposed energy indicated that van der Waals and non-polar interactions were predominant in the ligand-protein interactions. Further, crucial residues identified for hydrogen bond, salt bridge and hydrophobic interactions were Tyr35, Lys53, Glu71, Leu74, Leu75, Ile84, Met109, Leu167, Asp168 and Phe169. Our results indicate that stronger hydrophobic interaction of Si-BIRB with the binding site residues could be responsible for its greater binding affinity compared with BIRB.

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The design, synthesis, and evaluation of 8 hybrid DFG-out allosteric kinase inhibitors: A structural analysis of the binding interactions of Gleevec®, Nexavar®, and BIRB-796

Cited by 156 publications

References 35 publications

Structure–kinetic relationship study of CDK8/CycC specific compounds

Structure–kinetic relationship study of CDK8/CycC specific compounds

Characterization of interactions and pharmacophore development for DFG-out inhibitors to RET tyrosine kinase

Theoretical Characterization of Binding Mode of Organosilicon Inhibitor with p38: Docking, MD Simulation and MM/GBSA Free Energy Approach

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