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 Conventional chemical screening methods may miss potent small molecules because of their use of simple but outdated kits composed of recombinant enzyme proteins.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

In depth analysis of kinase cross screening data to identify chemical starting points for inhibition of the nek family of kinases

2017 ◽  
Author(s):  
Carrow I. Wells ◽  
Nirav R. Kapadia ◽  
Rafael M. Couñago ◽  
David H. Drewry
Keyword(s):  
Drug Discovery ◽  
Small Molecules ◽  
Small Molecule ◽  
Kinase Inhibitors ◽  
Biological Functions ◽  
Chemical Probes ◽  
High Quality ◽  
Depth Analysis ◽  
Number Of Citations ◽  
Shed Light

AbstractPotent, selective, and cell active small molecule kinase inhibitors are useful tools to help unravel the complexities of kinase signaling. As the biological functions of individual kinases become better understood, they can become targets of drug discovery efforts. The small molecules used to shed light on function can also then serve as chemical starting points in these drug discovery efforts. The Nek family of kinases has received very little attention, as judged by number of citations in PubMed, yet they appear to play many key roles and have been implicated in disease. Here we present our work to identify high quality chemical starting points that have emerged due to the increased incidence of broad kinome screening. We anticipate that this analysis will allow the community to progress towards the generation of chemical probes and eventually drugs that target members of the Nek family.

A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery

2013 ◽  
Vol 451 (2) ◽  
pp. 313-328 ◽  
Author(s):  
Yinghong Gao ◽  
Stephen P. Davies ◽  
Martin Augustin ◽  
Anna Woodward ◽  
Umesh A. Patel ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Drug Discovery ◽  
Small Molecules ◽  
Chemical Structure ◽  
Rational Design ◽  
Kinase Inhibitors ◽  
Biochemical Assays ◽  
Potential Applications ◽  
Specific Inhibitors ◽  
Target Effects

Despite the development of a number of efficacious kinase inhibitors, the strategies for rational design of these compounds have been limited by target promiscuity. In an effort to better understand the nature of kinase inhibition across the kinome, especially as it relates to off-target effects, we screened a well-defined collection of kinase inhibitors using biochemical assays for inhibitory activity against 234 active human kinases and kinase complexes, representing all branches of the kinome tree. For our study we employed 158 small molecules initially identified in the literature as potent and specific inhibitors of kinases important as therapeutic targets and/or signal transduction regulators. Hierarchical clustering of these benchmark kinase inhibitors on the basis of their kinome activity profiles illustrates how they relate to chemical structure similarities and provides new insights into inhibitor specificity and potential applications for probing new targets. Using this broad dataset, we provide a framework for assessing polypharmacology. We not only discover likely off-target inhibitor activities and recommend specific inhibitors for existing targets, but also identify potential new uses for known small molecules.

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 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 Synthetic Strategies of Pyrimidine-Based Scaffolds as Aurora Kinase and Polo-like Kinase Inhibitors

Molecules ◽  
2021 ◽  
Vol 26 (17) ◽  
pp. 5170
Author(s):  
Mrunal Jadhav ◽  
Kaksha Sankhe ◽  
Richie R. Bhandare ◽  
Zehra Edis ◽  
Samir Haj Bloukh ◽  
...  
Keyword(s):  
Small Molecules ◽  
Protein Kinases ◽  
Anticancer Drugs ◽  
Anticancer Agents ◽  
Kinase Inhibitors ◽  
Antitumor Agents ◽  
Aurora Kinase ◽  
Pyrimidine Ring ◽  
Pyrimidine Derivatives ◽  
Comprehensive Overview

The past few decades have witnessed significant progress in anticancer drug discovery. Small molecules containing heterocyclic moieties have attracted considerable interest for designing new antitumor agents. Of these, the pyrimidine ring system is found in multitude of drug structures, and being the building unit of DNA and RNA makes it an attractive scaffold for the design and development of anticancer drugs. Currently, 22 pyrimidine-containing entities are approved for clinical use as anticancer drugs by the FDA. An exhaustive literature search indicates several publications and more than 59 patents from the year 2009 onwards on pyrimidine derivatives exhibiting potent antiproliferative activity. These pyrimidine derivatives exert their activity via diverse mechanisms, one of them being inhibition of protein kinases. Aurora kinase (AURK) and polo-like kinase (PLK) are protein kinases involved in the regulation of the cell cycle. Within the numerous pyrimidine-based small molecules developed as anticancer agents, this review focuses on the pyrimidine fused heterocyclic compounds modulating the AURK and PLK proteins in different phases of clinical trials as anticancer agents. This article aims to provide a comprehensive overview of synthetic strategies for the preparation of pyrimidine derivatives and their associated biological activity on AURK/PLK. It will also present an overview of the synthesis of the heterocyclic-2-aminopyrimidine, 4-aminopyrimidine and 2,4-diaminopyrimidine scaffolds, and one of the pharmacophores in AURK/PLK inhibitors is described systematically.

scholarly journals Aminoacyl-tRNA Synthetases as Valuable Targets for Antimicrobial Drug Discovery

2021 ◽  
Vol 22 (4) ◽  
pp. 1750
Author(s):  
Luping Pang ◽  
Stephen D. Weeks ◽  
Arthur Van Aerschot
Keyword(s):  
Amino Acid ◽  
Drug Discovery ◽  
Binding Sites ◽  
Resistance Mechanisms ◽  
X Ray ◽  
Trna Synthetases ◽  
Aminoacyl Trna Synthetases ◽  
Inhibitory Mechanisms ◽  
Proof Reading ◽  
Reading Activities

Aminoacyl-tRNA synthetases (aaRSs) catalyze the esterification of tRNA with a cognate amino acid and are essential enzymes in all three kingdoms of life. Due to their important role in the translation of the genetic code, aaRSs have been recognized as suitable targets for the development of small molecule anti-infectives. In this review, following a concise discussion of aaRS catalytic and proof-reading activities, the various inhibitory mechanisms of reported natural and synthetic aaRS inhibitors are discussed. Using the expanding repository of ligand-bound X-ray crystal structures, we classified these compounds based on their binding sites, focusing on their ability to compete with the association of one, or more of the canonical aaRS substrates. In parallel, we examined the determinants of species-selectivity and discuss potential resistance mechanisms of some of the inhibitor classes. Combined, this structural perspective highlights the opportunities for further exploration of the aaRS enzyme family as antimicrobial targets.

scholarly journals A Perspective on Extreme Open Science: Companies Sharing Compounds without Restriction

2019 ◽  
Vol 24 (5) ◽  
pp. 505-514 ◽  
Author(s):  
David H. Drewry ◽  
Carrow I. Wells ◽  
William J. Zuercher ◽  
Timothy M. Willson
Keyword(s):  
Dark Matter ◽  
Drug Discovery ◽  
Small Molecules ◽  
Drug Targets ◽  
Scientific Community ◽  
Kinase Inhibitors ◽  
Open Science ◽  
Potential Drug ◽  
Potential Drug Targets ◽  
Shed Light

Although the human genome provides the blueprint for life, most of the proteins it encodes remain poorly studied. This perspective describes how one group of scientists, in seeking new targets for drug discovery, used open science through unrestricted sharing of small molecules to shed light on dark matter of the genome. Starting initially with a single pharmaceutical company before expanding to multiple companies, a precedent was established for sharing published kinase inhibitors as chemical tools. The integration of open science and kinase chemogenomics has supported the study of many new potential drug targets by the scientific community.

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 Extreme Open Science: Companies Sharing Compounds without Restriction

2018 ◽  
Author(s):  
David Drewry ◽  
Carrow Wells ◽  
William J Zuercher ◽  
Timothy Mark Willson
Keyword(s):  
Dark Matter ◽  
Drug Discovery ◽  
Small Molecules ◽  
Human Genome ◽  
Pharmaceutical Company ◽  
Drug Targets ◽  
Kinase Inhibitors ◽  
Open Science ◽  
New Targets ◽  
Shed Light

Although the human genome provides the blueprint for life, most of the proteins it encodes remain poorly studied. We describe how one group of scientists, in seeking new targets for drug discovery, used open science through unrestricted sharing of small molecules to shed light on dark matter of the genome. Starting initially with a single pharmaceutical company before expanding to multiple companies, a precedent was established for sharing published kinase inhibitors as chemical tools. As a result, new drug targets were identified and the science of kinase chemogenomics was established.

A REVIEW ON THE ROLE OF TYROSINE KINASE INHIBITORS AVAILABLE FOR THE MANAGEMENT OF CHRONIC MYELOID LEUKEMIA

2020 ◽  
Vol 7 (2) ◽  
pp. 205-211
Author(s):  
Kaynat Fatima ◽  
Syed Tasleem Raza ◽  
Ale Eba ◽  
Sanchita Srivastava ◽  
Farzana Mahdi
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Protein Kinases ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Line Treatment ◽  
First Line ◽  
First Line Treatment

The function of protein kinases is to transfer a γ-phosphate group from ATP to serine, threonine, or tyrosine residues. Many of these kinases are linked to the initiation and development of human cancer. The recent development of small molecule kinase inhibitors for the treatment of different types of cancer in clinical therapy has proven successful. Significantly, after the G-protein-coupled receptors, protein kinases are the second most active category of drug targets. Imatinib mesylate was the first tyrosine kinase inhibitor (TKI), approved for chronic myeloid leukemia (CML) treatment. Imatinib induces appropriate responses in ~60% of patients; with ~20% discontinuing therapy due to sensitivity, and ~20% developing drug resistance. The introduction of newer TKIs such as, nilotinib, dasatinib, bosutinib, and ponatinib has provided patients with multiple options. Such agents are more active, have specific profiles of side effects and are more likely to reach the necessary milestones. First-line treatment decisions must be focused on CML risk, patient preferences and comorbidities. Given the excellent result, half of the patients eventually fail to seek first-line treatment (due to discomfort or resistance), with many of them needing a third or even further therapy lines. In the present review, we will address the role of tyrosine kinase inhibitors in therapy for chronic myeloid leukemia.

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