Pocketome of Human Kinases: Prioritizing the ATP Binding Sites of (Yet) Untapped Protein Kinases for Drug Discovery

2015 ◽  
Vol 55 (3) ◽  
pp. 538-549 ◽  
Author(s):  
Andrea Volkamer ◽  
Sameh Eid ◽  
Samo Turk ◽  
Sabrina Jaeger ◽  
Friedrich Rippmann ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Protein Kinases ◽  
Binding Sites ◽  
Atp Binding

scholarly journals Druggable Transient Pockets in Protein Kinases

Molecules ◽  
2021 ◽  
Vol 26 (3) ◽  
pp. 651
Author(s):  
Koji Umezawa ◽  
Isao Kii
Keyword(s):  
Drug Discovery ◽  
Small Molecules ◽  
Protein Kinases ◽  
Binding Sites ◽  
Kinase Inhibitors ◽  
Screening Methods ◽  
Research Attention ◽  
Folding Process ◽  
Chemical Screening ◽  
Inhibitory Mechanisms

Drug discovery using small molecule inhibitors is reaching a stalemate due to low selectivity, adverse off-target effects and inevitable failures in clinical trials. Conventional chemical screening methods may miss potent small molecules because of their use of simple but outdated kits composed of recombinant enzyme proteins. Non-canonical inhibitors targeting a hidden pocket in a protein have received considerable research attention. Kii and colleagues identified an inhibitor targeting a transient pocket in the kinase DYRK1A during its folding process and termed it FINDY. FINDY exhibits a unique inhibitory profile; that is, FINDY does not inhibit the fully folded form of DYRK1A, indicating that the FINDY-binding pocket is hidden in the folded form. This intriguing pocket opens during the folding process and then closes upon completion of folding. In this review, we discuss previously established kinase inhibitors and their inhibitory mechanisms in comparison with FINDY. We also compare the inhibitory mechanisms with the growing concept of “cryptic inhibitor-binding sites.” These sites are buried on the inhibitor-unbound surface but become apparent when the inhibitor is bound. In addition, an alternative method based on cell-free protein synthesis of protein kinases may allow the discovery of small molecules that occupy these mysterious binding sites. Transitional folding intermediates would become alternative targets in drug discovery, enabling the efficient development of potent kinase inhibitors.

Comparison of the ATP Binding Sites of Protein Kinases Using Conformationally Diverse Bisindolylmaleimides

2005 ◽  
Vol 127 (33) ◽  
pp. 11699-11708 ◽  
Author(s):  
Stephen Bartlett ◽  
Godfrey S. Beddard ◽  
Richard M. Jackson ◽  
Veysel Kayser ◽  
Colin Kilner ◽  
...  
Keyword(s):  
Protein Kinases ◽  
Binding Sites ◽  
Atp Binding

scholarly journals Design of a Novel and Selective IRAK4 Inhibitor Using Topological Water Network Analysis and Molecular Modeling Approaches

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3136 ◽  
Author(s):  
Myeong Lee ◽  
Anand Balupuri ◽  
Ye-rim Jung ◽  
Sungwook Choi ◽  
Areum Lee ◽  
...  
Keyword(s):  
Protein Kinases ◽  
Binding Sites ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
General Structure ◽  
Interleukin 1 ◽  
Atp Binding ◽  
Chemical Library ◽  
Vitro Assay

Protein kinases are deeply involved in immune-related diseases and various cancers. They are a potential target for structure-based drug discovery, since the general structure and characteristics of kinase domains are relatively well-known. However, the ATP binding sites in protein kinases, which serve as target sites, are highly conserved, and thus it is difficult to develop selective kinase inhibitors. To resolve this problem, we performed molecular dynamics simulations on 26 kinases in the aqueous solution, and analyzed topological water networks (TWNs) in their ATP binding sites. Repositioning of a known kinase inhibitor in the ATP binding sites of kinases that exhibited a TWN similar to interleukin-1 receptor-associated kinase 4 (IRAK4) allowed us to identify a hit molecule. Another hit molecule was obtained from a commercial chemical library using pharmacophore-based virtual screening and molecular docking approaches. Pharmacophoric features of the hit molecules were hybridized to design a novel compound that inhibited IRAK4 at low nanomolar levels in the in vitro assay.

scholarly journals Consensus sequences for ATP-binding sites in protein kinases do not apply to diacylglycerol kinases

1994 ◽  
Vol 304 (2) ◽  
pp. 661-662 ◽  
Author(s):  
D Schaap ◽  
J van der Wal ◽  
W J van Blitterswijk
Keyword(s):  
Protein Kinases ◽  
Binding Sites ◽  
Atp Binding ◽  
Consensus Sequences

scholarly journals Bioinformatic and experimental survey of 14-3-3-binding sites

2010 ◽  
Vol 427 (1) ◽  
pp. 69-78 ◽  
Author(s):  
Catherine Johnson ◽  
Sandra Crowther ◽  
Margaret J. Stafford ◽  
David G. Campbell ◽  
Rachel Toth ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
Binding Sites ◽  
Histone Deacetylases ◽  
Cognitive Disorders ◽  
Logic Gates ◽  
Protein Families ◽  
Kinase C ◽  
Dependent Protein ◽  
Physiological Demands

More than 200 phosphorylated 14-3-3-binding sites in the literature were analysed to define 14-3-3 specificities, identify relevant protein kinases, and give insights into how cellular 14-3-3/phosphoprotein networks work. Mode I RXX(pS/pT)XP motifs dominate, although the +2 proline residue occurs in less than half, and LX(R/K)SX(pS/pT)XP is prominent in plant 14-3-3-binding sites. Proline at +1 is rarely reported, and such motifs did not stand up to experimental reanalysis of human Ndel1. Instead, we discovered that 14-3-3 interacts with two residues that are phosphorylated by basophilic kinases and located in the DISC1 (disrupted-in-schizophrenia 1)-interacting region of Ndel1 that is implicated in cognitive disorders. These data conform with the general findings that there are different subtypes of 14-3-3-binding sites that overlap with the specificities of different basophilic AGC (protein kinase A/protein kinase G/protein kinase C family) and CaMK (Ca2+/calmodulin-dependent protein kinase) protein kinases, and a 14-3-3 dimer often engages with two tandem phosphorylated sites, which is a configuration with special signalling, mechanical and evolutionary properties. Thus 14-3-3 dimers can be digital logic gates that integrate more than one input to generate an action, and coincidence detectors when the two binding sites are phosphorylated by different protein kinases. Paired sites are generally located within disordered regions and/or straddle either side of functional domains, indicating how 14-3-3 dimers modulate the conformations and/or interactions of their targets. Finally, 14-3-3 proteins bind to members of several multi-protein families. Two 14-3-3-binding sites are conserved across the class IIa histone deacetylases, whereas other protein families display differential regulation by 14-3-3s. We speculate that 14-3-3 dimers may have contributed to the evolution of such families, tailoring regulatory inputs to different physiological demands.

scholarly journals Selective Inhibition of DNA Replicase Assembly by a Non-natural Nucleotide: Exploiting the Structural Diversity of ATP-Binding Sites

2009 ◽  
Vol 5 (2) ◽  
pp. 183-194 ◽  
Author(s):  
Kevin Eng ◽  
Sarah K. Scouten-Ponticelli ◽  
Mark Sutton ◽  
Anthony Berdis
Keyword(s):  
Binding Sites ◽  
Structural Diversity ◽  
Selective Inhibition ◽  
Atp Binding ◽  
Dna Replicase
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