scholarly journals Case study: Paralog diverged features may help reduce off-target effects of drugs

2016 ◽  
Author(s):  
Zhining Sa ◽  
Jingqi Zhou ◽  
Yangyun Zou ◽  
Xun Gu
Keyword(s):  
Side Effects ◽  
Physicochemical Properties ◽  
Binding Sites ◽  
Drug Targets ◽  
Functional Divergence ◽  
Drug Binding ◽  
Type Ii ◽  
Glucagon Receptor ◽  
Protein Receptors ◽  
Glucagon Like Peptide 1

AbstractSide effects from targeted drugs is a serious concern. One reason is the nonselective binding of a drug to unintended proteins such as its paralogs, which are highly homologous in sequences and exhibit similar structures and drug-binding pockets. In this study, we analyzed amino acid residues with type-II functional divergence, i.e., sites that are conserved in sequence constraints but differ in physicochemical properties between paralogs, to identify targetable differences between two paralogs. We analyzed paralogous protein receptors in the glucagon-like subfamily, glucagon receptor (GCGR) and glucagon-like peptide-1 receptor (GLP-1R), which are clinically validated drug targets in patients with type 2 diabetes and exhibit divergence in ligands, showing opposing roles in regulating glucose homeostasis. We identified 8 residues related to type-II functional divergence, which are conserved in functional constraints but differ in physicochemical properties between GCGR and GLP-1R. We detected significant enrichment of predicted residues in binding sites of the antagonist MK-0893 to GCGR. We also identified a type-II functional divergence-related residue involved in ligand-specific effects that was critical for agonist-mediated activation of GLP-1R. We describe the important role of type-II functional divergence-related sites in paralog discrimination, enabling the identification of binding sites to reduce undesirable side effects and increase the target specificity of drugs.

scholarly journals Transport of Ketoprofen in Mammalian Blood Plasma

2021 ◽  
Author(s):  
Mateusz P. Czub ◽  
Ivan G. Shabalin ◽  
Wladek Minor
Keyword(s):  
Fatty Acids ◽  
Side Effects ◽  
Serum Albumin ◽  
Blood Plasma ◽  
Binding Sites ◽  
Drug Binding ◽  
Vascular Transport ◽  
Mammalian Blood ◽  
Drug Binding Sites ◽  
Binding Determinants

SummaryKetoprofen is a popular non-steroidal anti-inflammatory drug (NSAID) transported in the bloodstream mainly by serum albumin (SA). Ketoprofen is known to have multiple side effects and interactions with hundreds of other drugs, which might be related to its vascular transport by SA. Our work reveals that ketoprofen binds to a different subset of drug binding sites on human SA than has been observed for other species, despite the conservation of drug sites between species. We discuss potential reasons for the observed differences in the drug’s preferences for particular sites, including ketoprofen binding determinants in mammalian SAs and the effect of fatty acids on drug binding. The presented results show that the SA drug sites to which a particular drug binds cannot be easily predicted based only on a complex of SA from another species and the conservation of drug sites between species.

scholarly journals A complex suite of loci and elements in eukaryotic type II topoisomerases determine selective sensitivity to distinct poisoning agents

2019 ◽  
Vol 47 (15) ◽  
pp. 8163-8179 ◽  
Author(s):  
Tim R Blower ◽  
Afif Bandak ◽  
Amy S Y Lee ◽  
Caroline A Austin ◽  
John L Nitiss ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Amino Acid ◽  
Drug Targets ◽  
Topoisomerase Ii ◽  
Point Mutations ◽  
Amino Acid Position ◽  
Drug Binding ◽  
Type Ii ◽  
Resistance Mutations ◽  
Selective Sensitivity

AbstractType II topoisomerases catalyze essential DNA transactions and are proven drug targets. Drug discrimination by prokaryotic and eukaryotic topoisomerases is vital to therapeutic utility, but is poorly understood. We developed a next-generation sequencing (NGS) approach to identify drug-resistance mutations in eukaryotic topoisomerases. We show that alterations conferring resistance to poisons of human and yeast topoisomerase II derive from a rich mutational ‘landscape’ of amino acid substitutions broadly distributed throughout the entire enzyme. Both general and discriminatory drug-resistant behaviors are found to arise from different point mutations found at the same amino acid position and to occur far outside known drug-binding sites. Studies of selected resistant enzymes confirm the NGS data and further show that the anti-cancer quinolone vosaroxin acts solely as an intercalating poison, and that the antibacterial ciprofloxacin can poison yeast topoisomerase II. The innate drug-sensitivity of the DNA binding and cleavage region of human and yeast topoisomerases (particularly hTOP2β) is additionally revealed to be significantly regulated by the enzymes’ adenosine triphosphatase regions. Collectively, these studies highlight the utility of using NGS-based methods to rapidly map drug resistance landscapes and reveal that the nucleotide turnover elements of type II topoisomerases impact drug specificity.

scholarly journals Molecular Pharmacology of K2P Potassium Channels

2021 ◽  
Vol 55 (S3) ◽  
pp. 87-107
Keyword(s):  
Potassium Channels ◽  
Binding Sites ◽  
Drug Targets ◽  
Therapeutic Potential ◽  
Drug Binding ◽  
Channel Blockers ◽  
Molecular Pharmacology ◽  
K2p Channel ◽  
Channel Inhibition ◽  
K2p Channels

Potassium channels of the tandem of two-pore-domain (K2P) family were among the last potassium channels cloned. However, recent progress in understanding their physiological relevance and molecular pharmacology revealed their therapeutic potential and thus these channels evolved as major drug targets against a large variety of diseases. However, after the initial cloning of the fifteen family members there was a lack of potent and/or selective modulators. By now a large variety of K2P channel modulators (activators and blockers) have been described, especially for TASK-1, TASK-3, TREK-1, TREK2, TRAAK and TRESK channels. Recently obtained crystal structures of K2P channels, alanine scanning approaches to map drug binding sites, in silico experiments with molecular dynamics simulations (MDs) combined with electrophysiological studies to reveal the mechanism of channel inhibition/activation, yielded a good understanding of the molecular pharmacology of these channels. Besides summarizing drugs that were identified to modulate K2P channels, the main focus of this article is on describing the differential binding sites and mechanisms of channel modulation that are utilized by the different K2P channel blockers and activators.

scholarly journals LiP-Quant, an automated chemoproteomic approach to identify drug targets in complex proteomes

2019 ◽  
Author(s):  
Ilaria Piazza ◽  
Nigel Beaton ◽  
Roland Bruderer ◽  
Thomas Knobloch ◽  
Crystel Barbisan ◽  
...  
Keyword(s):  
Small Molecule ◽  
Binding Sites ◽  
Drug Target ◽  
Drug Targets ◽  
Target Identification ◽  
Limited Proteolysis ◽  
Drug Binding ◽  
Homologous Proteins ◽  
Protein Targets ◽  
Drug Target Identification

Chemoproteomics is a key technology to characterize the mode of action of drugs, as it directly identifies the protein targets of bioactive compounds and aids in developing optimized small-molecule compounds. Current unbiased approaches cannot directly pinpoint the interaction surfaces between ligands and protein targets. To address his limitation we have developed a new drug target deconvolution approach based on limited proteolysis coupled with mass spectrometry that works across species including human cells (LiP-Quant). LiP-Quant features an automated data analysis pipeline and peptide-level resolution for the identification of any small-molecule binding sites, Here we demonstrate drug target identification by LiP-Quant across compound classes, including compounds targeting kinases and phosphatases. We demonstrate that LiP-Quant estimates the half maximal effective concentration (EC50) of compound binding sites in whole cell lysates. LiP-Quant identifies targets of both selective and promiscuous drugs and correctly discriminates drug binding to homologous proteins. We finally show that the LiP-Quant technology identifies targets of a novel research compound of biotechnological interest.

Current Status and Future Perspective for Research on Medicinal Plants with Anticancerous Activity and Minimum Cytotoxic Value

2019 ◽  
Vol 20 (12) ◽  
pp. 1227-1243
Author(s):  
Hina Qamar ◽  
Sumbul Rehman ◽  
D.K. Chauhan
Keyword(s):  
Side Effects ◽  
Medicinal Plants ◽  
Anticancer Agents ◽  
Drug Targets ◽  
Psidium Guajava ◽  
Current Status ◽  
Future Perspective ◽  
Wide Range

Cancer is the second leading cause of morbidity and mortality worldwide. Although chemotherapy and radiotherapy enhance the survival rate of cancerous patients but they have several acute toxic effects. Therefore, there is a need to search for new anticancer agents having better efficacy and lesser side effects. In this regard, herbal treatment is found to be a safe method for treating and preventing cancer. Here, an attempt has been made to screen some less explored medicinal plants like Ammania baccifera, Asclepias curassavica, Azadarichta indica, Butea monosperma, Croton tiglium, Hedera nepalensis, Jatropha curcas, Momordica charantia, Moringa oleifera, Psidium guajava, etc. having potent anticancer activity with minimum cytotoxic value (IC50 >3μM) and lesser or negligible toxicity. They are rich in active phytochemicals with a wide range of drug targets. In this study, these medicinal plants were evaluated for dose-dependent cytotoxicological studies via in vitro MTT assay and in vivo tumor models along with some more plants which are reported to have IC50 value in the range of 0.019-0.528 mg/ml. The findings indicate that these plants inhibit tumor growth by their antiproliferative, pro-apoptotic, anti-metastatic and anti-angiogenic molecular targets. They are widely used because of their easy availability, affordable price and having no or sometimes minimal side effects. This review provides a baseline for the discovery of anticancer drugs from medicinal plants having minimum cytotoxic value with minimal side effects and establishment of their analogues for the welfare of mankind.

scholarly journals DNA G-quadruplexes for native mass spectrometry in potassium: a database of validated structures in electrospray-compatible conditions

2021 ◽  
Author(s):  
Anirban Ghosh ◽  
Eric Largy ◽  
Valérie Gabelica
Keyword(s):  
Mass Spectrometry ◽  
Drug Targets ◽  
Native Mass Spectrometry ◽  
Drug Binding ◽  
Quadruplex Dna ◽  
Dna Structures ◽  
Nmr Structures ◽  
G Quadruplex ◽  
Screening Assays

Abstract G-quadruplex DNA structures have become attractive drug targets, and native mass spectrometry can provide detailed characterization of drug binding stoichiometry and affinity, potentially at high throughput. However, the G-quadruplex DNA polymorphism poses problems for interpreting ligand screening assays. In order to establish standardized MS-based screening assays, we studied 28 sequences with documented NMR structures in (usually ∼100 mM) potassium, and report here their circular dichroism (CD), melting temperature (Tm), NMR spectra and electrospray mass spectra in 1 mM KCl/100 mM trimethylammonium acetate. Based on these results, we make a short-list of sequences that adopt the same structure in the MS assay as reported by NMR, and provide recommendations on using them for MS-based assays. We also built an R-based open-source application to build and consult a database, wherein further sequences can be incorporated in the future. The application handles automatically most of the data processing, and allows generating custom figures and reports. The database is included in the g4dbr package (https://github.com/EricLarG4/g4dbr) and can be explored online (https://ericlarg4.github.io/G4_database.html).

scholarly journals Targeting the GPR119/incretin axis: a promising new therapy for metabolic-associated fatty liver disease

2021 ◽  
Vol 26 (1) ◽  
Author(s):  
Jianan Zhao ◽  
Yu Zhao ◽  
Yiyang Hu ◽  
Jinghua Peng
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Drug Targets ◽  
Metabolic Dysfunction ◽  
Multiple Organs ◽  
Glucose And Lipid Metabolism ◽  
Potential Therapeutic Role ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

AbstractIn the past decade, G protein-coupled receptors have emerged as drug targets, and their physiological and pathological effects have been extensively studied. Among these receptors, GPR119 is expressed in multiple organs, including the liver. It can be activated by a variety of endogenous and exogenous ligands. After GPR119 is activated, the cell secretes a variety of incretins, including glucagon-like peptide-1 and glucagon-like peptide-2, which may attenuate the metabolic dysfunction associated with fatty liver disease, including improving glucose and lipid metabolism, inhibiting inflammation, reducing appetite, and regulating the intestinal microbial system. GPR119 has been a potential therapeutic target for diabetes mellitus type 2 for many years, but its role in metabolic dysfunction associated fatty liver disease deserves further attention. In this review, we discuss relevant research and current progress in the physiology and pharmacology of the GPR119/incretin axis and speculate on the potential therapeutic role of this axis in metabolic dysfunction associated with fatty liver disease, which provides guidance for transforming experimental research into clinical applications.

scholarly journals Eosinophils as the source of uterine nuclear type II estrogen binding sites.

1984 ◽  
Vol 259 (5) ◽  
pp. 2697-2700
Author(s):  
C R Lyttle ◽  
K L Medlock ◽  
D M Sheehan
Keyword(s):  
Binding Sites ◽  
Type Ii ◽  
Estrogen Binding

scholarly journals Crystal structures of aconitase X enzymes from bacteria and archaea provide insights into the molecular evolution of the aconitase superfamily

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Seiya Watanabe ◽  
Yohsuke Murase ◽  
Yasunori Watanabe ◽  
Yasuhiro Sakurai ◽  
Kunihiko Tajima
Keyword(s):  
Molecular Evolution ◽  
Agrobacterium Tumefaciens ◽  
Crystal Structures ◽  
Epr Spectroscopy ◽  
Binding Sites ◽  
Active Sites ◽  
Type I ◽  
Type Ii ◽  
Thermococcus Kodakarensis ◽  
Evolutionary Scenario

AbstractAconitase superfamily members catalyze the homologous isomerization of specific substrates by sequential dehydration and hydration and contain a [4Fe-4S] cluster. However, monomeric and heterodimeric types of function unknown aconitase X (AcnX) have recently been characterized as a cis-3-hydroxy-L-proline dehydratase (AcnXType-I) and mevalonate 5-phosphate dehydratase (AcnXType-II), respectively. We herein elucidated the crystal structures of AcnXType-I from Agrobacterium tumefaciens (AtAcnX) and AcnXType-II from Thermococcus kodakarensis (TkAcnX) without a ligand and in complex with substrates. AtAcnX and TkAcnX contained the [2Fe-2S] and [3Fe-4S] clusters, respectively, conforming to UV and EPR spectroscopy analyses. The binding sites of the [Fe-S] cluster and substrate were clearlydifferent from those that were completely conserved in other aconitase enzymes; however, theoverall structural frameworks and locations of active sites were partially similar to each other.These results provide novel insights into the evolutionary scenario of the aconitase superfamilybased on the recruitment hypothesis.

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