scholarly journals Evolution of kinase polypharmacology across HSP90 drug discovery

2020 ◽  
Author(s):  
Albert A. Antolin ◽  
Paul A. Clarke ◽  
Ian Collins ◽  
Paul Workman ◽  
Bissan Al-Lazikani
Keyword(s):  
Drug Discovery ◽  
Drug Design ◽  
Small Molecules ◽  
Protein Kinases ◽  
Experimental Methods ◽  
Experimental Characterization ◽  
Hsp90 Inhibitors ◽  
Target Drug ◽  
Clinical Candidate

AbstractMost small molecules interact with several target proteins but this polypharmacology is seldom comprehensively investigated or explicitly exploited during drug discovery. Here, we use computational and experimental methods to systematically characterize the kinase cross-pharmacology of representative HSP90 inhibitors. We demonstrate that the resorcinol clinical candidates ganetespib and, to a lesser extent, luminespib, display unique off-target kinase pharmacology as compared to other HSP90 inhibitors. We also demonstrate that polypharmacology evolved during the optimisation to discover luminespib and that the hit, leads and clinical candidate all have different polypharmacological profiles. We conclude that the submicromolar target inhibition of protein kinases by ganetespib may have potential clinical significance and we recommend the computational and experimental characterization of polypharmacology earlier in drug discovery projects to unlock new multi-target drug design opportunities.

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 Conventional chemical screening methods may miss potent small molecules because of their use of simple but outdated kits composed of recombinant enzyme proteins.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.

scholarly journals Block relevance (BR) analysis and polarity descriptors in property-based drug design

ADMET & DMPK ◽  
2018 ◽  
Vol 6 (3) ◽  
pp. 215-224 ◽  
Author(s):  
Giuseppe Ermondi ◽  
Giulia Caron
Keyword(s):  
Drug Discovery ◽  
Drug Design ◽  
Information Content

Block Relevance (BR) analysis is a tool to interpret QSPR/PLS models which can provide the information content of any physicochemical determinant used in property-based drug discovery; its application for the characterization of experimental polarity descriptors is discussed.

scholarly journals Optimized methods for IL-17A refolding and anti-IL17A Fab production for co-crystallization with small molecules

BioTechniques ◽  
2020 ◽  
Vol 69 (1) ◽  
pp. 70-76
Author(s):  
Xiaoyun Meng ◽  
Lanjun Zhang ◽  
Hong Wei ◽  
Furong Li ◽  
Lihua Hu ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Small Molecules ◽  
Small Molecule ◽  
Yield Enhancement ◽  
High Affinity ◽  
Interleukin 17A ◽  
Affinity Peptide ◽  
First Time ◽  
Essential Prerequisite

Refolding of human interleukin 17A (IL-17A) has been reported; however, the key refolding protocol was not robust enough to deliver consistent results and to be easily scaled up for crystallization. Here we report an optimized refolding method for IL-17A. Although co-crystal structures of IL-17A with ligands have been obtained with a high-affinity peptide and an anti-IL-17A Fab as stabilizers, neither the production yield nor the characterization of the IL-17A/Fab complex was reported. To facilitate co-crystallization of IL-17A with small-molecule compounds derived from our DNA encoded library, we also describe the method for yield enhancement of anti-IL-17A Fab production and characterize the IL-17A/Fab complex for the first time, providing an essential prerequisite for structure-based drug discovery targeting IL-17A.

scholarly journals Nuclear Magnetic Resonance Spectroscopyan Evolutionary Approach to Drug Design

2007 ◽  
Vol 4 (3) ◽  
pp. 294-301
Author(s):  
Neeraj Upmanyu ◽  
Gopal Garg ◽  
Archana Dolly ◽  
Pradeep Mishra
Keyword(s):  
Nuclear Magnetic Resonance ◽  
Drug Discovery ◽  
Magnetic Resonance ◽  
Drug Design ◽  
Small Molecules ◽  
Pharmaceutical Research ◽  
Three Dimensional ◽  
Drug Discovery And Development ◽  
4D Nmr ◽  
Nuclear Magnetic

Ever since Nuclear Magnetic Resonance (NMR) spectroscopy hit the analytical scene; its capabilities and applications continue to evolve. Originally designed as a way to verify the structure of relatively small compounds, the technology of NMR has exploded and become a valuable means for studying protein structure. NMR has proved to be a valuable tool in pharmaceutical research, as it has entered new arena of drug discovery and structural genomics. NMR can provide information on the three-dimensional structures of small molecules in solution, high-molecular-weight complexes, and the details of enzyme mechanisms that can be used to aid in drug design. In the present scenario, the availability of high magnetic fields; improved software, high resolution probes, and electronics; more versatile pulse programmers; and most importantly the development of 2D, 3D and 4D NMR, have revolutionized the field of drug discovery and development.

scholarly journals MM-PBSA and the Importance of the Dielectric Constant for Kinase Drug Design

2020 ◽  
Author(s):  
Melanie Schneider ◽  
Gilles Labesse
Keyword(s):  
Dielectric Constant ◽  
Drug Discovery ◽  
Drug Design ◽  
Small Molecules ◽  
Design Process ◽  
Critical Role ◽  
Binding Pocket ◽  
Solvation Energy ◽  
Drug Discovery And Development ◽  
The Common

Predicting the interactions between a set of small molecules and its target plays a critical role in drug discovery and development. Especially in later stages of the drug design process, when a reduced set of molecules is in focus, reliable and accurate binding affinity estimations are important for targeted modifications of given lead molecules.<div><div>Current limitations in affinity prediction originate from the lack of accurate estimates for solvation energy and entropy. MM-PBSA and the related MM-GBSA aim at providing better estimates.</div><div>From our studies we infer that the common approach using one dielectric constant for the binding pocket may be misleading (here in the case of a kinase), especially when designed ligands/drugs contain charges. Thus, a range of selected values for the solute dielectric constant is preferred for better and more reliable comparisons.</div></div>

scholarly journals MM-PBSA and the Importance of the Dielectric Constant for Kinase Drug Design

2020 ◽  
Author(s):  
Melanie Schneider ◽  
Gilles Labesse
Keyword(s):  
Dielectric Constant ◽  
Drug Discovery ◽  
Drug Design ◽  
Small Molecules ◽  
Design Process ◽  
Critical Role ◽  
Binding Pocket ◽  
Solvation Energy ◽  
Drug Discovery And Development ◽  
The Common

Predicting the interactions between a set of small molecules and its target plays a critical role in drug discovery and development. Especially in later stages of the drug design process, when a reduced set of molecules is in focus, reliable and accurate binding affinity estimations are important for targeted modifications of given lead molecules.<div><div>Current limitations in affinity prediction originate from the lack of accurate estimates for solvation energy and entropy. MM-PBSA and the related MM-GBSA aim at providing better estimates.</div><div>From our studies we infer that the common approach using one dielectric constant for the binding pocket may be misleading (here in the case of a kinase), especially when designed ligands/drugs contain charges. Thus, a range of selected values for the solute dielectric constant is preferred for better and more reliable comparisons.</div></div>

Experimental Characterization of the Reliability of 3-Terminal Dual-Damascene Copper Interconnect Trees

2002 ◽  
Vol 716 ◽  
Author(s):  
C. L. Gan ◽  
C. V. Thompson ◽  
K. L. Pey ◽  
W. K. Choi ◽  
F. Wei ◽  
...  
Keyword(s):  
Stress Conditions ◽  
Experimental Characterization ◽  
Contact Lines ◽  
Tree Structures ◽  
Similar Test ◽  
Dual Damascene ◽  
Copper Interconnect ◽  
Test Conditions

AbstractElectromigration experiments have been carried out on simple Cu dual-damascene interconnect tree structures consisting of straight via-to-via (or contact-to-contact) lines with an extra via in the middle of the line. As with Al-based interconnects, the reliability of a segment in this tree strongly depends on the stress conditions of the connected segment. Beyond this, there are important differences in the results obtained under similar test conditions for Al-based and Cu-based interconnect trees. These differences are thought to be associated with variations in the architectural schemes of the two metallizations. The absence of a conducting electromigrationresistant overlayer in Cu technology, and the possibility of liner rupture at stressed vias lead to significant differences in tree reliabilities in Cu compared to Al.

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