scholarly journals Prediction of allosteric sites and signaling: Insights from benchmarking datasets

Patterns ◽  
2021 ◽  
pp. 100408
Author(s):  
Nan Wu ◽  
Léonie Strömich ◽  
Sophia N. Yaliraki
Keyword(s):  
Allosteric Sites

Approach in improving potency and selectivity of kinase inhibitors: Allosteric kinase inhibitors

2020 ◽  
Vol 21 ◽  
Author(s):  
Shangfei Wei ◽  
Tianming Zhao ◽  
Jie Wang ◽  
Xin Zhai
Keyword(s):  
Protein Interactions ◽  
Kinase Inhibitors ◽  
Binding Modes ◽  
Allosteric Inhibitors ◽  
Wide Range ◽  
Allosteric Sites ◽  
Protein Functions ◽  
Regulate Protein

: Allostery is an efficient and particular regulatory mechanism to regulate protein functions. Different from conserved orthosteric sites, allosteric sites have distinctive functional mechanism to form the complex regulatory network. In drug discovery, kinase inhibitors targeting the allosteric pockets have received extensive attention for the advantages of high selectivity and low toxicity. The approval of trametinib as the first allosteric inhibitor validated that allosteric inhibitors could be used as effective therapeutic drugs for treatment of diseases. To date, a wide range of allosteric inhibitors have been identified. In this perspective, we outline different binding modes and potential advantages of allosteric inhibitors. In the meantime, the research processes of typical and novel allosteric inhibitors are described briefly in terms of structureactivity relationships, ligand-protein interactions and in vitro and in vivo activity. Additionally, challenges as well as opportunities are presented.

Tuning Down the Pain – An Overview of Allosteric Modulation of Opioid Receptors: Mechanisms of Modulation, Allosteric Sites, Modulator Syntheses

2020 ◽  
Vol 20 (31) ◽  
pp. 2852-2865 ◽  
Author(s):  
Damian Bartuzi ◽  
Tomasz M. Wróbel ◽  
Agnieszka A. Kaczor ◽  
Dariusz Matosiuk
Keyword(s):  
Side Effects ◽  
Opioid Receptors ◽  
Pain Perception ◽  
Allosteric Modulation ◽  
Allosteric Modulators ◽  
Signaling Mechanisms ◽  
Main Target ◽  
Allosteric Sites ◽  
Biased Signaling ◽  
Opioid Signaling

Opioid signaling plays a central role in pain perception. As such, it remains the main target in the development of antinociceptive agents, despite serious side effects involved. In recent years, hopes for improved opioid painkillers are rising, together with our understanding of allosterism and biased signaling mechanisms. In this review, we focus on recently discovered allosteric modulators of opioid receptors, insights into phenomena underlying their action, as well as on how they extend our understanding of mechanisms of previously known compounds. A brief overlook of their synthesis is also presented.

Spatial relationships among the active and allosteric sites of carbamoyl-phosphate synthetase

1985 ◽  
Vol 13 (2) ◽  
pp. 98-109 ◽  
Author(s):  
Philip G. Kasprzyk ◽  
Eric Whalen-Pederson ◽  
Paul M. Anderson ◽  
Joseph J. Villafranca
Keyword(s):  
Spatial Relationships ◽  
Carbamoyl Phosphate Synthetase ◽  
Carbamoyl Phosphate ◽  
Allosteric Sites

scholarly journals The structural basis for cancer drug interactions with the catalytic and allosteric sites of SAMHD1

2018 ◽  
Author(s):  
Kirsten M. Knecht ◽  
Olga Buzovetsky ◽  
Constanze Schneider ◽  
Dominique Thomas ◽  
Vishok Srikanth ◽  
...  
Keyword(s):  
Cancer Therapy ◽  
Genome Stability ◽  
Viral Infections ◽  
Structural Basis ◽  
Cancer Drug ◽  
Allosteric Site ◽  
Nucleotide Analogues ◽  
Future Design ◽  
Nucleotide Analogue ◽  
Allosteric Sites

AbstractSAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase (dNTPase) that depletes cellular dNTPs in non-cycling cells to promote genome stability and to inhibit retroviral and herpes viral replication. In addition to being substrates, cellular nucleotides also allosterically regulate SAMHD1 activity. Recently, it was shown that high expression levels of SAMHD1 are also correlated with significantly worse patient responses to nucleotide analogue drugs important for treating a variety of cancers, including Acute Myeloid Leukemia (AML). In this study, we used biochemical, structural, and cellular methods to examine the interactions of various cancer drugs with SAMHD1. We found that both the catalytic and the allosteric sites of SAMHD1 are sensitive to sugar modifications of the nucleotide analogs, with the allosteric site being significantly more restrictive. We crystallized cladribine-TP, clofarabine-TP, fludarabine-TP, vidarabine-TP, cytarabine-TP, and gemcitabine-TP in the catalytic pocket of SAMHD1. We find that all of these drugs are substrates of SAMHD1 and that the efficacy of most of these drugs is affected by SAMHD1 activity. Of the nucleotide analogues tested, only cladribine-TP with a deoxyribose sugar efficiently induced the catalytically active SAMHD1 tetramer. Together, these results establish a detailed framework for understanding the substrate specificity and allosteric activation of SAMHD1 with regards to nucleotide analogues, which can be used to improve current cancer and antiviral therapies.SignificanceNucleoside analogue drugs are widely used to treat a variety of cancers and viral infections. With an essential role in regulating the nucleotide pool in the cell by degrading cellular nucleotides, SAMHD1 has the potential to decrease the cellular concentration of frequently prescribed nucleotide analogues and thereby decrease their clinical efficacy in cancer therapy. To improve future nucleotide analogue treatments, it is important to understand SAMHD1 interactions with these drugs. Our work thoroughly examines the extent to which nucleotide analogues interact with the catalytic and allosteric sites of SAMHD1. This work contributes to the assessment of SAMHD1 as a potential therapeutic target for cancer therapy and the future design of SAMHD1 modulators that might improve the efficacy of existing therapies.

scholarly journals Synthesis and Pharmacological Evaluation of Novel 2,3,4,5-tetrahydro[1,3]diazepino[1,2-a]benzimidazole Derivatives as Promising Anxiolytic and Analgesic Agents

Molecules ◽  
2021 ◽  
Vol 26 (19) ◽  
pp. 6049
Author(s):  
Dmitriy V. Maltsev ◽  
Alexander A. Spasov ◽  
Pavel M. Vassiliev ◽  
Maria O. Skripka ◽  
Mikhail V. Miroshnikov ◽  
...  
Keyword(s):  
In Silico Analysis ◽  
Chloroacetic Acid ◽  
Benzimidazole Derivatives ◽  
Neutral Medium ◽  
Tail Flick ◽  
Resonance Spectroscopy ◽  
Chemical Structures ◽  
Motor Activities ◽  
Allosteric Sites ◽  
Analgesic Agents

A number of novel 2,3,4,5-tetrahydro[1,3]diazepino[1,2-a]benzimidazole derivatives 2 were obtained by alkylation mainly in the 1H-tautomeric form of 2,3,4,5-tetrahydro[1,3]diazepino[1,2-a]benzimidazole or its 8,9-dimethyl-substituted analog 4-chlorobenzyl bromide, 4-chloroacetic acid fluoroanilide, and 4-tert-butylphenacyl bromide in neutral medium. Compounds 3 were cyclized and synthesized earlier with 11-phenacyl-substituted diazepino[1,2-a]benzimidazoles upon heating in conc. HBr. The chemical structures of the compounds were clarified by using the 1H Nuclear Magnetic Resonance Spectroscopy (1H-NMR) technique. Anxiolytic properties were evaluated using the elevated plus maze (EPM) and open field (OF) tests. The analgesic effect of compounds was estimated with the tail flick (TF) and hot plate (HP) methods. Besides, possible the influence of the test compounds on motor activities of the animals was examined by the Grid, Wire, and Rotarod tests. Compounds 2d and 3b were the most active due to their prominent analgesic and anxiolytic potentials, respectively. The results of the performed in silico analysis showed that the high anxiolytic activity of compound 3b is explained by the combination of a pronounced interaction mainly with the benzodiazepine site of the GABAA receptor with a prominent interaction with both the specific and allosteric sites of the 5-HT2A receptor.

Identification of Allosteric Sites in Rabbit Phosphofructo-1-kinase†

Biochemistry ◽  
1999 ◽  
Vol 38 (49) ◽  
pp. 16407-16412 ◽  
Author(s):  
Yali Li ◽  
Diana Rivera ◽  
Wei Ru ◽  
Dhammika Gunasekera ◽  
Robert G. Kemp
Keyword(s):  
Allosteric Sites

scholarly journals The structural basis for cancer drug interactions with the catalytic and allosteric sites of SAMHD1

2018 ◽  
Vol 115 (43) ◽  
pp. E10022-E10031 ◽  
Author(s):  
Kirsten M. Knecht ◽  
Olga Buzovetsky ◽  
Constanze Schneider ◽  
Dominique Thomas ◽  
Vishok Srikanth ◽  
...  
Keyword(s):  
Genome Stability ◽  
Structural Basis ◽  
Cancer Drug ◽  
Allosteric Site ◽  
Nucleotide Analogs ◽  
Antiviral Therapies ◽  
Allosteric Sites ◽  
Catalytically Active ◽  
Deoxynucleoside Triphosphate ◽  
Patient Responses

SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase (dNTPase) that depletes cellular dNTPs in noncycling cells to promote genome stability and to inhibit retroviral and herpes viral replication. In addition to being substrates, cellular nucleotides also allosterically regulate SAMHD1 activity. Recently, it was shown that high expression levels of SAMHD1 are also correlated with significantly worse patient responses to nucleotide analog drugs important for treating a variety of cancers, including acute myeloid leukemia (AML). In this study, we used biochemical, structural, and cellular methods to examine the interactions of various cancer drugs with SAMHD1. We found that both the catalytic and the allosteric sites of SAMHD1 are sensitive to sugar modifications of the nucleotide analogs, with the allosteric site being significantly more restrictive. We crystallized cladribine-TP, clofarabine-TP, fludarabine-TP, vidarabine-TP, cytarabine-TP, and gemcitabine-TP in the catalytic pocket of SAMHD1. We found that all of these drugs are substrates of SAMHD1 and that the efficacy of most of these drugs is affected by SAMHD1 activity. Of the nucleotide analogs tested, only cladribine-TP with a deoxyribose sugar efficiently induced the catalytically active SAMHD1 tetramer. Together, these results establish a detailed framework for understanding the substrate specificity and allosteric activation of SAMHD1 with regard to nucleotide analogs, which can be used to improve current cancer and antiviral therapies.

scholarly journals Inhibitory Activity of Quercetin 3-O-Arabinofuranoside and 2-Oxopomolic Acid Derived from Malus domestica on Soluble Epoxide Hydrolase

Molecules ◽  
2020 ◽  
Vol 25 (18) ◽  
pp. 4352
Author(s):  
In Sook Cho ◽  
Jang Hoon Kim ◽  
Yunjia Lin ◽  
Xiang Dong Su ◽  
Jong Seong Kang ◽  
...  
Keyword(s):  
Malus Domestica ◽  
Epoxide Hydrolase ◽  
Soluble Epoxide Hydrolase ◽  
Corosolic Acid ◽  
Allosteric Sites ◽  
Ic50 Values ◽  
Cardiovascular Tests ◽  
Potential Inhibitors ◽  
Molecular Docking And Dynamics

Flavonoids and triterpenoids were revealed to be the potential inhibitors on soluble epoxide hydrolase (sEH). The aim of this study is to reveal sEH inhibitors from Fuji apples. A flavonoid and three triterpenoids derived from the fruit of Malus domestica were identified as quercetin-3-O-arabinoside (1), ursolic acid (2), corosolic acid (3), and 2-oxopomolic acid (4). They had half-maximal inhibitory concentration of the inhibitors (IC50) values of 39.3 ± 3.4, 84.5 ± 9.5, 51.3 ± 4.9, and 11.4 ± 2.7 μM, respectively, on sEH. The inhibitors bound to allosteric sites of enzymes in mixed (1) and noncompetitive modes (2–4). Molecular simulations were carried out for inhibitors 1 and 4 to calculate the binding force of ligands to receptors. The inhibitors bound to the left (1) and right (4) pockets next to the enzyme’s active site. Based on analyses of their molecular docking and dynamics, it was shown that inhibitors 1 and 4 can stably bind sEH at 1 bar and 300 K. Finally, inhibitors 1 and 4 are promising candidates for further studies using cell-based assays and in vivo cardiovascular tests.

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