Benzofuran Small Molecules as Potential Inhibitors of Human Protein Kinases. A Review

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 Conventional chemical screening methods may miss potent small molecules because of their use of simple but outdated kits composed of recombinant enzyme proteins.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

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HomoKinase: A Curated Database of Human Protein Kinases

ISRN Computational Biology ◽

10.1155/2013/417634 ◽

2013 ◽

Vol 2013 ◽

pp. 1-5 ◽

Cited By ~ 11

Author(s):

Suresh Subramani ◽

Saranya Jayapalan ◽

Raja Kalpana ◽

Jeyakumar Natarajan

Keyword(s):

Gene Ontology ◽

Protein Kinases ◽

Kinase Activity ◽

Query Protein ◽

Amino Acid Sequences ◽

Human Protein ◽

Biological Information ◽

Functional Domain ◽

Comprehensive Collection ◽

Search Tool

HomoKinase database is a comprehensive collection of curated human protein kinases and their relevant biological information. The entries in the database are curated by three criteria: HGNC approval, gene ontology-based biological process (protein phosphorylation), and molecular function (ATP binding and kinase activity). For a given query protein kinase name, the database provides its official symbol, full name, other known aliases, amino acid sequences, functional domain, gene ontology, pathways assignments, and drug compounds. In addition, as a search tool, it enables the retrieval of similar protein kinases with specific family, subfamily, group, and domain combinations and tabulates the information. The present version contains 498 curated human protein kinases and links to other popular databases.

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Computer-aided molecular design of new potential inhibitors of protein kinases using of 4-methyl-benzoic acid as a linker

SDRP Journal of Computational Chemistry & Molecular Modelling ◽

10.25177/jccmm.3.2.ra.577 ◽

2019 ◽

Vol 3 (2) ◽

pp. 285-293

Author(s):

Aliaksandr V. Faryna ◽

Еlena N. Kalinichenko

Keyword(s):

Benzoic Acid ◽

Protein Kinases ◽

Molecular Design ◽

Computer Aided ◽

Potential Inhibitors

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Biochemical investigations of the mechanism of action of small molecules ZL006 and IC87201 as potential inhibitors of the nNOS-PDZ/PSD-95-PDZ interactions

Scientific Reports ◽

10.1038/srep12157 ◽

2015 ◽

Vol 5 (1) ◽

Cited By ~ 20

Author(s):

Anders Bach ◽

Søren W. Pedersen ◽

Liam A. Dorr ◽

Gary Vallon ◽

Isabelle Ripoche ◽

...

Keyword(s):

Small Molecules ◽

Mechanism Of Action ◽

Potential Inhibitors

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Human Protein Kinases and Obesity

Obesity and Lipotoxicity - Advances in Experimental Medicine and Biology ◽

10.1007/978-3-319-48382-5_5 ◽

2017 ◽

pp. 111-134 ◽

Cited By ~ 12

Author(s):

Atilla Engin

Keyword(s):

Protein Kinases ◽

Human Protein

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Targeting the GRP78-Dependant SARS-CoV-2 Cell Entry by Peptides and Small Molecules

Bioinformatics and Biology Insights ◽

10.1177/1177932220965505 ◽

2020 ◽

Vol 14 ◽

pp. 117793222096550

Author(s):

Loubna Allam ◽

Fatima Ghrifi ◽

Hakmi Mohammed ◽

Naima El Hafidi ◽

Rachid El Jaoudi ◽

...

Keyword(s):

Small Molecules ◽

Binding Sites ◽

Epigallocatechin Gallate ◽

Host Cells ◽

Spike Protein ◽

Target Cells ◽

Binding Affinities ◽

Rapid Spread ◽

Inhibitor Compounds ◽

Potential Inhibitors

The global burden of infections and the rapid spread of viral diseases show the need for new approaches in the prevention and development of effective therapies. To this end, we aimed to explore novel inhibitor compounds that can stop replication or decrease the viral load of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), for which there is currently no approved treatment. Besides using the angiotensin-converting enzyme (ACE2) receptor as a main gate, the CoV-2 can bind to the glucose-regulating protein 78 (GRP78) receptor to get into the cells to start an infection. Here, we report potential inhibitors comprising small molecules and peptides that could interfere with the interaction of SARS-CoV-2 and its target cells by blocking the recognition of the GRP78 cellular receptor by the viral Spike protein. These inhibitors were discovered through an approach of in silico screening of available databases of bioactive peptides and polyphenolic compounds and the analysis of their docking modes. This process led to the selection of 9 compounds with optimal binding affinities to the target sites. The peptides (satpdb18674, satpdb18446, satpdb12488, satpdb14438, and satpdb28899) act on regions III and IV of the viral Spike protein and on its binding sites in GRP78. However, 4 polyphenols such as epigallocatechin gallate (EGCG), homoeriodictyol, isorhamnetin, and curcumin interact, in addition to the Spike protein and its binding sites in GRP78, with the ATPase domain of GRP78. Our work demonstrates that there are at least 2 approaches to block the spread of SARS-CoV-2 by preventing its fusion with the host cells via GRP78.

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