scholarly journals Chemical Starting Matter for HNF4α Ligand Discovery and Chemogenomics

2020 ◽  
Vol 21 (21) ◽  
pp. 7895
Author(s):  
Isabelle Meijer ◽  
Sabine Willems ◽  
Xiaomin Ni ◽  
Jan Heering ◽  
Apirat Chaikuad ◽  
...  
Keyword(s):  
Drug Target ◽  
Metabolic Diseases ◽  
Therapeutic Potential ◽  
Hepatocyte Nuclear Factor ◽  
Structure Activity ◽  
Starting Point ◽  
Ligand Discovery ◽  
Elevated Activity ◽  
Hepatocyte Nuclear Factor 4Α ◽  
Micromolar Range

Hepatocyte nuclear factor 4α (HNF4α) is a ligand-sensing transcription factor and presents as a potential drug target in metabolic diseases and cancer. In humans, mutations in the HNF4α gene cause maturity-onset diabetes of the young (MODY), and the elevated activity of this protein has been associated with gastrointestinal cancers. Despite the high therapeutic potential, available ligands and structure–activity relationship knowledge for this nuclear receptor are scarce. Here, we disclose a chemically diverse collection of orthogonally validated fragment-like activators as well as inverse agonists, which modulate HNF4α activity in a low micromolar range. These compounds demonstrate the druggability of HNF4α and thus provide a starting point for medicinal chemistry as well as an early tool for chemogenomics.

scholarly journals Discovery of Diaryl Ether Substituted Tetrahydrophthalazinones as TbrPDEB1 Inhibitors Following Structure-Based Virtual Screening

2021 ◽  
Vol 8 ◽  
Author(s):  
Erik de Heuvel ◽  
Albert J. Kooistra ◽  
Ewald Edink ◽  
Sjors van Klaveren ◽  
Jeffrey Stuijt ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Drug Target ◽  
Future Design ◽  
Cellular Processes ◽  
Novel Treatment ◽  
Structure Activity ◽  
Diaryl Ether ◽  
Starting Point ◽  
Pde Inhibitors ◽  
Important Structure

Several members of the 3′,5′-cyclic nucleotide phosphodiesterase (PDE) family play an essential role in cellular processes, which has labeled them as interesting targets for various diseases. The parasitic protozoan Trypanosoma brucei, causative agent of human African trypanosomiasis, contains several cyclic AMP specific PDEs from which TbrPDEB1 is validated as a drug target. The recent discovery of selective TbrPDEB1 inhibitors has increased their potential for a novel treatment for this disease. Compounds characterized by a rigid biphenyl tetrahydrophthalazinone core structure were used as starting point for the exploration of novel TbrPDEB1 inhibitors. Using a virtual screening campaign and structure-guided design, diaryl ether substituted phthalazinones were identified as novel TbrPDEB1 inhibitors with IC50 values around 1 μM against T. brucei. This study provides important structure-activity relationship (SAR) information for the future design of effective parasite-specific PDE inhibitors.

scholarly journals Malonate in the nucleotide-binding site traps human AKAP18γ/δ in a novel conformational state

2016 ◽  
Vol 72 (8) ◽  
pp. 591-597 ◽  
Author(s):  
Kaare Bjerregaard-Andersen ◽  
Ellen Østensen ◽  
John D. Scott ◽  
Kjetil Taskén ◽  
Jens Preben Morth
Keyword(s):  
Drug Target ◽  
Therapeutic Potential ◽  
Conformational State ◽  
Atomic Resolution ◽  
Macromolecular Complex ◽  
Spatiotemporal Resolution ◽  
Anchoring Proteins ◽  
Excellent Starting Point ◽  
Starting Point ◽  
Kinase A

A-kinase anchoring proteins (AKAPs) are a family of proteins that provide spatiotemporal resolution of protein kinase A (PKA) phosphorylation. In the myocardium, PKA and AKAP18γ/δ are found in complex with sarcoendoplasmic reticulum Ca2+-ATPase 2 (SERCA2) and phospholamban (PLB). This macromolecular complex provides a means by which anchored PKA can dynamically regulate cytoplasmic Ca2+release and re-uptake. For this reason, AKAP18γ/δ presents an interesting drug target with therapeutic potential in cardiovascular disease. The crystal structure of the central domain of human AKAP18γ has been determined at the atomic resolution of 1.25 Å. This first structure of human AKAP18γ is trapped in a novel conformation by a malonate molecule bridging the important R-loop with the 2H phosphoesterase motif. Although the physiological substrate of AKAP18γ is currently unknown, a potential proton wire deep in the central binding crevice has been indentified, leading to bulk solvent below the R-loop. Malonate complexed with AKAP18γ at atomic resolution provides an excellent starting point for structure-guided drug design.

scholarly journals Development of Pyridine-Based Inhibitors for the Human Vaccinia-Related Kinases 1 and 2

2019 ◽  
Author(s):  
Ricardo Serafim ◽  
Fernando de Souza Gama ◽  
Caio dos Reis ◽  
Stanley Vasconcelos ◽  
André Santiago ◽  
...  
Keyword(s):  
Cell Division ◽  
Protein Kinases ◽  
Neurological Disorders ◽  
Therapeutic Potential ◽  
Binding Mode ◽  
Crystallographic Analysis ◽  
Activity Relationship ◽  
Cellular Functions ◽  
Structure Activity ◽  
Starting Point

<div> <p>Vaccinia-related kinases 1 and 2 (VRK1 and VRK2) are human Ser/Thr protein kinases associated with increased cell division and neurological disorders. Nevertheless, the cellular functions of these proteins are not fully understood. Despite their therapeutic potential, there are no inhibitors available for VRK1 or VRK2. We report here the discovery and elaboration of an aminopyridine scaffold as a basis for VRK1 and VRK2 inhibitors. The most potent compounds displayed <i>K</i><sub>D</sub> values of 190 nM and 401 nM for VRK1 and VRK2, respectively. Differences in compound binding mode and substituent preferences between the two VRKs were identified by the series structure-activity relationship combined with the crystallographic analysis of key compounds. We expect that our results will serve as a starting point for the design of specific and potent inhibitors against each of the two VRKs based on a pyridine scaffold.</p> </div>

scholarly journals Development of Pyridine-Based Inhibitors for the Human Vaccinia-Related Kinases 1 and 2

2019 ◽  
Author(s):  
Ricardo Serafim ◽  
Fernando de Souza Gama ◽  
Caio dos Reis ◽  
Stanley Vasconcelos ◽  
André Santiago ◽  
...  
Keyword(s):  
Cell Division ◽  
Protein Kinases ◽  
Neurological Disorders ◽  
Therapeutic Potential ◽  
Binding Mode ◽  
Crystallographic Analysis ◽  
Activity Relationship ◽  
Cellular Functions ◽  
Structure Activity ◽  
Starting Point

<div> <p>Vaccinia-related kinases 1 and 2 (VRK1 and VRK2) are human Ser/Thr protein kinases associated with increased cell division and neurological disorders. Nevertheless, the cellular functions of these proteins are not fully understood. Despite their therapeutic potential, there are no inhibitors available for VRK1 or VRK2. We report here the discovery and elaboration of an aminopyridine scaffold as a basis for VRK1 and VRK2 inhibitors. The most potent compounds displayed <i>K</i><sub>D</sub> values of 190 nM and 401 nM for VRK1 and VRK2, respectively. Differences in compound binding mode and substituent preferences between the two VRKs were identified by the series structure-activity relationship combined with the crystallographic analysis of key compounds. We expect that our results will serve as a starting point for the design of specific and potent inhibitors against each of the two VRKs based on a pyridine scaffold.</p> </div>

scholarly journals A Structural Approach into Drug Discovery Based on Autophagy

Life ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 526
Author(s):  
Sung-Min Kang ◽  
Do-Hee Kim
Keyword(s):  
High Throughput Screening ◽  
Drug Target ◽  
Metabolic Diseases ◽  
Structural Information ◽  
Screening Methods ◽  
Structural Studies ◽  
Intracellular Degradation ◽  
Structure Activity ◽  
Related Proteins ◽  
Novel Drug

Autophagy is a lysosome-dependent intracellular degradation machinery that plays an essential role in the regulation of cellular homeostasis. As many studies have revealed that autophagy is related to cancer, neurodegenerative diseases, metabolic diseases, and so on, and it is considered as a promising drug target. Recent advances in structural determination and computational technologies provide important structural information on essential autophagy-related proteins. Combined with high-throughput screening methods, structure-activity relationship studies have led to the discovery of molecules that modulate autophagy. In this review, we summarize the recent structural studies on autophagy-related proteins and the discovery of modulators, indicating that targeting autophagy can be utilized as an effective strategy for novel drug development.

A common mechanism links activities of butyrate in the colon

2017 ◽  
Author(s):  
Mohit S. Verma ◽  
Michael J. Fink ◽  
Gabriel L Salmon ◽  
Nadine Fornelos ◽  
Takahiro E. Ohara ◽  
...  
Keyword(s):  
Stem Cells ◽  
Histone Deacetylases ◽  
Biological Activities ◽  
Short Chain Fatty Acids ◽  
Common Mechanism ◽  
Epithelial Stem Cells ◽  
Degree Of Unsaturation ◽  
Structure Activity ◽  
Starting Point ◽  
New Compounds

Two biological activities of butyrate in the colon (suppression of proliferation of colonic epithelial stem cells and inflammation) correlate with inhibition of histone deacetylases. Cellular and biochemical studies of molecules similar in structure to butyrate, but different in molecular details (functional groups, chain-length, deuteration, oxidation level, fluorination, or degree of unsaturation) demonstrated that these activities were sensitive to molecular structure, and were compatible with the hypothesis that butyrate acts by binding to the Zn<sup>2+</sup> in the catalytic site of histone deacetylases. Structure-activity relationships drawn from a set of 36 compounds offer a starting point for the design of new compounds targeting the inhibition of histone deacetylases. The observation that butyrate was more potent than other short-chain fatty acids is compatible with the hypothesis that crypts evolved (at least in part), to separate stem cells at the base of crypts from butyrate produced by commensal bacteria.

Bacterial Polyphosphate Kinases Revisited: Role in Pathogenesis and Therapeutic Potential

2019 ◽  
Vol 20 (3) ◽  
pp. 292-301 ◽  
Author(s):  
Lalit Kumar Gautam ◽  
Prince Sharma ◽  
Neena Capalash
Keyword(s):  
Drug Target ◽  
Bacterial Infections ◽  
Therapeutic Potential ◽  
Wide Distribution ◽  
Medical Community ◽  
Polyphosphate Kinase ◽  
Potential Drug Target ◽  
Potential Drug ◽  
Resistant Strains ◽  
Structural Aspects

Bacterial infections have always been an unrestrained challenge to the medical community due to the rise of multi-drug tolerant and resistant strains. Pioneering work on Escherichia coli polyphosphate kinase (PPK) by Arthur Kornberg has generated great interest in this polyphosphate (PolyP) synthesizing enzyme. PPK has wide distribution among pathogens and is involved in promoting pathogenesis, stress management and susceptibility to antibiotics. Further, the absence of a PPK orthologue in humans makes it a potential drug target. This review covers the functional and structural aspects of polyphosphate kinases in bacterial pathogens. A description of molecules being designed against PPKs has been provided, challenges associated with PPK inhibitor design are highlighted and the strategies to enable development of efficient drug against this enzyme have also been discussed.

scholarly journals Flavonoids from the Genus Euphorbia: Isolation, Structure, Pharmacological Activities and Structure–Activity Relationships

2021 ◽  
Vol 14 (5) ◽  
pp. 428
Author(s):  
Douglas Kemboi Magozwi ◽  
Mmabatho Dinala ◽  
Nthabiseng Mokwana ◽  
Xavier Siwe-Noundou ◽  
Rui W. M. Krause ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Antioxidant Properties ◽  
Structure Activity Relationship ◽  
Biological Properties ◽  
Therapeutic Agents ◽  
Skeletal Structure ◽  
Activity Relationship ◽  
Hydroxyl Groups ◽  
Structure Activity ◽  
Review Reports

Plants of the genus Euphorbia are widely distributed across temperate, tropical and subtropical regions of South America, Asia and Africa with established Ayurvedic, Chinese and Malay ethnomedical records. The present review reports the isolation, occurrence, phytochemistry, biological properties, therapeutic potential and structure–activity relationship of Euphorbia flavonoids for the period covering 2000–2020, while identifying potential areas for future studies aimed at development of new therapeutic agents from these plants. The findings suggest that the extracts and isolated flavonoids possess anticancer, antiproliferative, antimalarial, antibacterial, anti-venom, anti-inflammatory, anti-hepatitis and antioxidant properties and have different mechanisms of action against cancer cells. Of the investigated species, over 80 different types of flavonoids have been isolated to date. Most of the isolated flavonoids were flavonols and comprised simple O-substitution patterns, C-methylation and prenylation. Others had a glycoside, glycosidic linkages and a carbohydrate attached at either C-3 or C-7, and were designated as d-glucose, l-rhamnose or glucorhamnose. The structure–activity relationship studies showed that methylation of the hydroxyl groups on C-3 or C-7 reduces the activities while glycosylation loses the activity and that the parent skeletal structure is essential in retaining the activity. These constituents can therefore offer potential alternative scaffolds towards development of new Euphorbia-based therapeutic agents.

scholarly journals Identification of 3,4-Dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothiazin-6-imine Derivatives as Novel Selective Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase

2021 ◽  
Vol 22 (13) ◽  
pp. 7236
Author(s):  
Endah Dwi Hartuti ◽  
Takaya Sakura ◽  
Mohammed S. O. Tagod ◽  
Eri Yoshida ◽  
Xinying Wang ◽  
...  
Keyword(s):  
Drug Target ◽  
De Novo ◽  
Dihydroorotate Dehydrogenase ◽  
Chemical Library ◽  
New Class ◽  
De Novo Biosynthesis ◽  
Starting Point ◽  
Novel Drugs ◽  
Low Toxicity ◽  
Fourth Step

Plasmodium falciparum’s resistance to available antimalarial drugs highlights the need for the development of novel drugs. Pyrimidine de novo biosynthesis is a validated drug target for the prevention and treatment of malaria infection. P. falciparum dihydroorotate dehydrogenase (PfDHODH) catalyzes the oxidation of dihydroorotate to orotate and utilize ubiquinone as an electron acceptor in the fourth step of pyrimidine de novo biosynthesis. PfDHODH is targeted by the inhibitor DSM265, which binds to a hydrophobic pocket located at the N-terminus where ubiquinone binds, which is known to be structurally divergent from the mammalian orthologue. In this study, we screened 40,400 compounds from the Kyoto University chemical library against recombinant PfDHODH. These studies led to the identification of 3,4-dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothiazin-6-imine and its derivatives as a new class of PfDHODH inhibitor. Moreover, the hit compounds identified in this study are selective for PfDHODH without inhibition of the human enzymes. Finally, this new scaffold of PfDHODH inhibitors showed growth inhibition activity against P. falciparum 3D7 with low toxicity to three human cell lines, providing a new starting point for antimalarial drug development.

scholarly journals DsbA-L deficiency in T cells promotes diet-induced thermogenesis through suppressing IFN-γ production

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Haiyan Zhou ◽  
Xinyi Peng ◽  
Jie Hu ◽  
Liwen Wang ◽  
Hairong Luo ◽  
...  
Keyword(s):  
T Cells ◽  
Adipose Tissue ◽  
T Cell ◽  
Energy Homeostasis ◽  
Metabolic Diseases ◽  
Therapeutic Potential ◽  
Whole Body ◽  
Brown Adipose ◽  
Ifn Γ ◽  
Diet Induced Thermogenesis

AbstractAdipose tissue-resident T cells have been recognized as a critical regulator of thermogenesis and energy expenditure, yet the underlying mechanisms remain unclear. Here, we show that high-fat diet (HFD) feeding greatly suppresses the expression of disulfide-bond A oxidoreductase-like protein (DsbA-L), a mitochondria-localized chaperone protein, in adipose-resident T cells, which correlates with reduced T cell mitochondrial function. T cell-specific knockout of DsbA-L enhances diet-induced thermogenesis in brown adipose tissue (BAT) and protects mice from HFD-induced obesity, hepatosteatosis, and insulin resistance. Mechanistically, DsbA-L deficiency in T cells reduces IFN-γ production and activates protein kinase A by reducing phosphodiesterase-4D expression, leading to increased BAT thermogenesis. Taken together, our study uncovers a mechanism by which T cells communicate with brown adipocytes to regulate BAT thermogenesis and whole-body energy homeostasis. Our findings highlight a therapeutic potential of targeting T cells for the treatment of over nutrition-induced obesity and its associated metabolic diseases.

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