Epigenetic relevant chemical space: a chemoinformatic characterization of inhibitors of DNA methyltransferases

RSC Advances ◽  
2015 ◽  
Vol 5 (106) ◽  
pp. 87465-87476 ◽  
Author(s):  
Eli Fernández-de Gortari ◽  
José L. Medina-Franco
Keyword(s):  
Chemical Space ◽  
Dna Methyltransferases

The first comprehensive exploration of the epigenetic relevant chemical space is reported in this work with a special emphasis on inhibitors of DNA methyltransferases.

scholarly journals BIOFACQUIM: A Mexican Compound Database of Natural Products

Biomolecules ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 31 ◽  
Author(s):  
B. Pilón-Jiménez ◽  
Fernanda Saldívar-González ◽  
Bárbara Díaz-Eufracio ◽  
José Medina-Franco
Keyword(s):  
Natural Products ◽  
Drug Discovery ◽  
Physicochemical Properties ◽  
Chemical Space ◽  
Structural Diversity ◽  
Proof Of Concept ◽  
Molecular Fingerprints ◽  
The Public ◽  
Compound Database

Compound databases of natural products have a major impact on drug discovery projects and other areas of research. The number of databases in the public domain with compounds with natural origins is increasing. Several countries, Brazil, France, Panama and, recently, Vietnam, have initiatives in place to construct and maintain compound databases that are representative of their diversity. In this proof-of-concept study, we discuss the first version of BIOFACQUIM, a novel compound database with natural products isolated and characterized in Mexico. We discuss its construction, curation, and a complete chemoinformatic characterization of the content and coverage in chemical space. The profile of physicochemical properties, scaffold content, and diversity, as well as structural diversity based on molecular fingerprints is reported. BIOFACQUIM is available for free.

scholarly journals Comprehensive structure-function characterization of DNMT3B and DNMT3A reveals distinctive de novo DNA methylation mechanisms

2020 ◽  
Author(s):  
Linfeng Gao ◽  
Max Emperle ◽  
Yiran Guo ◽  
Sara A Grimm ◽  
Wendan Ren ◽  
...  
Keyword(s):  
Dna Methylation ◽  
De Novo ◽  
Target Selection ◽  
Dna Methyltransferases ◽  
Recognition Mechanism ◽  
Layered Substrate ◽  
Structural Enzymology ◽  
Catalytic Loop ◽  
Methylation Patterns

AbstractMammalian DNA methylation patterns are established by two de novo DNA methyltransferases DNMT3A and DNMT3B, which exhibit both redundant and distinctive methylation activities. However, the related molecular basis remains undetermined. Through comprehensive structural, enzymology and cellular characterization of DNMT3A and DNMT3B, we here report a multi-layered substrate-recognition mechanism underpinning their divergent genomic methylation activities. A hydrogen bond in the catalytic loop of DNMT3B causes a lower CpG specificity than DNMT3A, while the interplay of target recognition domain and homodimeric interface fine-tunes the distinct target selection between the two enzymes, with Lysine 777 of DNMT3B acting as a unique sensor of the +1 flanking base. The divergent substrate preference between DNMT3A and DNMT3B provides an explanation for site-specific epigenomic alterations seen in ICF syndrome with DNMT3B mutations. Together, this study reveals crucial and distinctive substrate-readout mechanisms of the two DNMT3 enzymes, implicative of their differential roles during development and pathogenesis.

scholarly journals Identification and characterization of an atypical Gαs-biased β2AR agonist that fails to evoke airway smooth muscle cell tachyphylaxis

2021 ◽  
Vol 118 (49) ◽  
pp. e2026668118
Author(s):  
Donghwa Kim ◽  
Alina Tokmakova ◽  
Lauren K. Lujan ◽  
Hannah R. Strzelinski ◽  
Nicholas Kim ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Chemical Space ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Airway Smooth Muscle Cell ◽  
Functional Studies ◽  
G Protein Coupled ◽  
Identification And Characterization

G protein–coupled receptors display multifunctional signaling, offering the potential for agonist structures to promote conformational selectivity for biased outputs. For β2-adrenergic receptors (β2AR), unbiased agonists stabilize conformation(s) that evoke coupling to Gαs (cyclic adenosine monophosphate [cAMP] production/human airway smooth muscle [HASM] cell relaxation) and β-arrestin engagement, the latter acting to quench Gαs signaling, contributing to receptor desensitization/tachyphylaxis. We screened a 40-million-compound scaffold ranking library, revealing unanticipated agonists with dihydroimidazolyl-butyl-cyclic urea scaffolds. The S-stereoisomer of compound C1 shows no detectable β-arrestin engagement/signaling by four methods. However, C1-S retained Gαs signaling—a divergence of the outputs favorable for treating asthma. Functional studies with two models confirmed the biasing: β2AR-mediated cAMP signaling underwent desensitization to the unbiased agonist albuterol but not to C1-S, and desensitization of HASM cell relaxation was observed with albuterol but not with C1-S. These HASM results indicate biologically pertinent biasing of C1-S, in the context of the relevant physiologic response, in the human cell type of interest. Thus, C1-S was apparently strongly biased away from β-arrestin, in contrast to albuterol and C5-S. C1-S structural modeling and simulations revealed binding differences compared with unbiased epinephrine at transmembrane (TM) segments 3,5,6,7 and ECL2. C1-S (R2 = cyclohexane) was repositioned in the pocket such that it lost a TM6 interaction and gained a TM7 interaction compared with the analogous unbiased C5-S (R2 = benzene group), which appears to contribute to C1-S biasing away from β-arrestin. Thus, an agnostic large chemical-space library identified agonists with receptor interactions that resulted in relevant signal splitting of β2AR actions favorable for treating obstructive lung disease.

scholarly journals DNA Methylation in Lysogens of Pathogenic Burkholderia spp. Requires Prophage Induction and Is Restricted to Excised Phage DNA

2005 ◽  
Vol 187 (3) ◽  
pp. 1196-1200 ◽  
Author(s):  
M. J. Smith ◽  
J. A. Jeddeloh
Keyword(s):  
Dna Methylation ◽  
Cytosine Methylation ◽  
Dna Methyltransferases ◽  
Burkholderia Mallei ◽  
Prophage Induction ◽  
Host Chromosome ◽  
Burkholderia Thailandensis ◽  
Specific Phage ◽  
Phage Dna

ABSTRACT Burkholderia mallei-specific phage ΦE125 encodes DNA methyltransferases in both the lysogenic and replication modules within its genome. Characterization of DNA methylation in recombinant systems, specifically in ΦE125 lysogenic strains of B. mallei and Burkholderia thailandensis, revealed that, upon induction, cytosine methylation was targeted specifically to the phage episome but not the phage provirus or the host chromosome.

scholarly journals Comprehensive machine learning based study of the chemical space of herbicides

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Davor Oršolić ◽  
Vesna Pehar ◽  
Tomislav Šmuc ◽  
Višnja Stepanić
Keyword(s):  
Natural Products ◽  
Predictive Models ◽  
Chemical Space ◽  
Data Set ◽  
Modes Of Action ◽  
Molecular Features ◽  
Global Increase ◽  
Screening Platform ◽  
Weed Resistance

AbstractWidespread use of herbicides results in the global increase in weed resistance. The rotational use of herbicides according to their modes of action (MoAs) and discovery of novel phytotoxic molecules are the two strategies used against the weed resistance. Herein, Random Forest modeling was used to build predictive models and establish comprehensive characterization of structure–activity relationships underlying herbicide classifications according to their MoAs and weed selectivity. By combining the predictive models with herbicide-likeness rules defined by selected molecular features (numbers of H-bond acceptors and donors, logP, topological and relative polar surface area, and net charge), the virtual stepwise screening platform is proposed for characterization of small weight molecules for their phytotoxic properties. The screening cascade was applied on the data set of phytotoxic natural products. The obtained results may be valuable for refinement of herbicide rotational program as well as for discovery of novel herbicides primarily among natural products as a source for molecules of novel structures and novel modes of action and translocation profiles as compared with the synthetic compounds.

scholarly journals Structuring Chemical Space: Similarity-Based Characterization of the PubChem Database

2010 ◽  
Vol 29 (1-2) ◽  
pp. 37-49 ◽  
Author(s):  
Giovanni Cincilla ◽  
Michael Thormann ◽  
Miquel Pons
Keyword(s):  
Chemical Space ◽  
Pubchem Database

scholarly journals Isolation, Genomic and Metabolomic Characterization of Streptomyces tendae VITAKN with Quorum Sensing Inhibitory Activity from Southern India

2020 ◽  
Vol 8 (1) ◽  
pp. 121 ◽  
Author(s):  
Nabila Mohammed Ishaque ◽  
Ilia Burgsdorf ◽  
Jessie James Limlingan Malit ◽  
Subhasish Saha ◽  
Roberta Teta ◽  
...  
Keyword(s):  
Quorum Sensing ◽  
Natural Product ◽  
Chemical Space ◽  
Sequence Similarity ◽  
Gc Content ◽  
Gene Clusters ◽  
Biosynthetic Gene ◽  
Isolation And Characterization ◽  
Streptomyces Tendae

Streptomyces are among the most promising genera in terms of production ability to biosynthesize a variety of bioactive secondary metabolites with pharmaceutical interest. Coinciding with the increase in genomic sequencing of these bacteria, mining of their genomes for biosynthetic gene clusters (BGCs) has become a routine component of natural product discovery. Herein, we describe the isolation and characterization of a Streptomyces tendae VITAKN with quorum sensing inhibitory (QSI) activity that was isolated from southern coastal part of India. The nearly complete genome consists of 8,621,231bp with a GC content of 72.2%. Sequence similarity networks of the BGCs detected from this strain against the Minimum Information about a Biosynthetic Gene Cluster (MIBiG) database and 3365 BGCs predicted by antiSMASH analysis of publicly available complete Streptomyces genomes were generated through the BiG-SCAPE-CORASON platform to evaluate its biosynthetic novelty. Crude extract analysis using high-performance liquid chromatography connected to high resolution tandem mass spectrometry (HPLC-HRMS/MS) and dereplication through the Global Natural Product Social Molecular Networking (GNPS) online workflow resulted in the identification of cyclic dipeptides (2, 5-diketopiperazines, DKPs) in the extract, which are known to possess QSI activity. Our results highlight the potential of genome mining coupled with LC-HRMS/MS and in silico tools (GNPS) as a valid approach for the discovery of novel QSI lead compounds. This study also provides the biosynthetic diversity of BGCs and an assessment of the predicted chemical space yet to be discovered.

scholarly journals Characterization of SIRT1/DNMTs Functions and LINE-1 Methylation in Patients with Age-Related Macular Degeneration

2019 ◽  
Vol 8 (2) ◽  
pp. 159 ◽  
Author(s):  
Andrea Maugeri ◽  
Martina Barchitta ◽  
Matteo Fallico ◽  
Niccolò Castellino ◽  
Michele Reibaldi ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Macular Degeneration ◽  
Methylation Level ◽  
Surrogate Marker ◽  
Dna Methyltransferases ◽  
Sirtuin 1 ◽  
Age Related Macular Degeneration ◽  
Clinical Biomarkers ◽  
Age Related

Previous studies proposed the application of DNA methylation signatures as clinical biomarkers of age-related macular degeneration (AMD). However, the characterization of Long Interspersed Nuclear Element-1 (LINE-1) methylation levels—a surrogate marker of global DNA methylation—in AMD patients has not been investigated so far. In the present study, we first characterized DNA methyltransferases (DNMTs) and Sirtuin 1 (SIRT1) functions in blood samples of 40 AMD patients and 10 age- and sex-matched controls. Then, we evaluated whether changes in DNMTs functions were associated with different LINE-1 methylation levels in leukocyte DNA. We demonstrated that total DNMTs activity was 48% higher in AMD patients than in controls (p = 0.005). AMD patients also exhibited up-regulation of DNMT1 and DNMT3B expression (FC = 2.6; p = 0.003 and FC = 2.4; p = 0.018, respectively). In line with increased DNMTs functions, the LINE-1 methylation level was higher in AMD patients than in controls (mean = 69.10%; SE = 0.68 vs. mean = 65.73%; SE = 0.59; p = 0.020). All p-values were adjusted by Bonferroni correction. In AMD patients, LINE-1 methylation level was positively associated with total DNMTs activity (r = 0.694; p < 0.001), DNMT1 (r = 0.579; p < 0.001), and DNMT3B (r = 0.521; p = 0.001) expression. Our results encourage further large-size prospective research to understand the relationship between LINE-1 methylation and AMD aetiology, and its usefulness in the clinical setting.

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