Chemical Biology is a relatively new field, and as such is not yet simply or succinctly defined. It includes such a wide range of fundamental problems that this commentary could only include just a few snapshots of potential areas of interest. Overarching themes and selected recent successes and ideas in chemical biology are described to illustrate broadly the scope of the field, but should not be taken as exhaustive. The Chemical Biology Section of Chemistry Central Journal is pleased to receive manuscripts describing research into all and any aspects of the subject.
The accumulation of unfolded proteins in the endoplasmic reticulum (ER) is
caused by many disease-relevant conditions, inducing conserved signaling
events collectively known as the unfolded protein response. When ER stress is
excessive or prolonged, cell death (usually occurring by apoptosis) is
triggered. We undertook a chemical biology approach for investigating
mechanisms of ER stress-induced cell death. Using a cell-based high throughput
screening assay to identify compounds that rescued a neuronal cell line from
thapsigargin-induced cell death, we identified benzodiazepinones that
selectively inhibit cell death caused by inducers of ER stress (thapsigargin
and tunicamycin) but not by inducers of extrinsic (tumor necrosis factor) or
intrinsic (mitochondrial) cell death pathways. The compounds displayed
activity in several cell lines and primary cultured neurons. Mechanism of
action studies revealed that these compounds inhibit ER stress-induced
activation of p38 MAPK and kinases responsible for c-Jun phosphorylation.
Active benzodiazepinones suppressed cell death at the level of apoptotic
signal kinase-1 (ASK1) within the IRE1 pathway but without directly inhibiting
the kinase activity of ASK1 or >400 other kinases tested. Rather...
Small-molecule fluorescent probes embody an essential facet of chemical biology. Although numerous compounds are known, the ensemble of fluorescent probes is based on a modest collection of modular “core” dyes. The elaboration of these dyes with diverse chemical moieties is enabling the precise interrogation of biochemical and biological systems. The importance of fluorescence-based technologies in chemical biology elicits a necessity to understand the major classes of small-molecule fluorophores. Here, we examine the chemical and photophysical properties of oft-used fluorophores, and highlight classic and contemporary examples in which utility has been built upon these scaffolds.
Systems pharmacology is an emergent area that studies drug action across multiple scales of complexity, from molecular and cellular to tissue and organism levels. There is a critical need to develop network-based approaches to integrate the growing body of chemical biology knowledge with network biology. Here, we report ChemProt, a disease chemical biology database, which is based on a compilation of multiple chemical–protein annotation resources, as well as disease-associated protein–protein interactions (PPIs). We assembled more than 700 000 unique chemicals with biological annotation for 30 578 proteins. We gathered over 2-million chemical–protein interactions, which were integrated in a quality scored human PPI network of 428 429 interactions. The PPI network layer allows for studying disease and tissue specificity through each protein complex. ChemProt can assist in the in silico evaluation of environmental chemicals, natural products and approved drugs, as well as the selection of new compounds based on their activity profile against most known biological targets, including those related to adverse drug events. Results from the disease chemical biology database associate citalopram, an antidepressant, with osteogenesis imperfect and leukemia and bisphenol A...
The explosion of scientific interest in protein kinase-mediated signaling networks has led to the infusion of new chemical methods and their applications related to the analysis of phosphorylation pathways. We highlight some of these chemical biology approaches across three areas. First, we discuss the development of chemical tools to modulate the activity of protein kinases to explore kinase mechanisms and their contributions to phosphorylation events and cellular processes. Second, we describe chemical techniques developed in the past few years to dissect the structural and functional effects of phosphate modifications at specific sites in proteins. Third, we cover newly developed molecular imaging approaches to elucidate the spatiotemporal aspects of phosphorylation cascades in live cells. Exciting advances in our understanding of protein phosphorylation have been obtained with these chemical biology approaches, but continuing opportunities for technological innovation remain.
There is a critical need for improving the level of chemistry awareness in systems biology. The data and information related to modulation of genes and proteins by small molecules continue to accumulate at the same time as simulation tools in systems biology and whole body physiologically-based pharmacokinetics (PBPK) continue to evolve. We called this emerging area at the interface between chemical biology and systems biology systems chemical biology, SCB (Oprea et al., 2007).
Chemical biology and the techniques the field encompasses provide
scientists with the means to address biological questions in ever evolving and
technically sophisticated ways. They facilitate the dissection of molecular
mechanisms of cell phenomena on timescales not achievable by other means.
Libraries of small molecules, bioorthogonal chemistries and technical advances
in mass-spectrometry techniques enable the modern chemical biologist to tackle
even the most difficult of biological questions. It is because of their broad
applicability that these approaches are well suited to systems less tractable to
more classical genetic methods. As such, the parasite community has embraced
them with great success. Some of these successes and the continuing evolution of
chemical biology applied to apicomplexans will be discussed.
Chromatin is extensively chemically modified and thereby acts as a dynamic signaling platform controlling gene function. Chromatin regulation is integral to cell differentiation, lineage commitment and organism development, whereas chromatin dysregulation can lead to age-related and neurodegenerative disorders as well as cancer. Investigating chromatin biology presents a unique challenge, as the issue spans many disciplines, including cell and systems biology, biochemistry and molecular biophysics. In recent years, the application of chemical biology methods for investigating chromatin processes has gained considerable traction. Indeed, chemical biologists now have at their disposal powerful chemical tools that allow chromatin biology to be scrutinized at the level of the cell all the way down to the single chromatin fiber. Here we present recent examples of how this rapidly expanding palette of chemical tools is being used to paint a detailed picture of chromatin function in organism development and disease.
Ventricular tachyarrhythmia (VT) is one of the most serious adverse drug reactions leading to death. The in vitro assessment of the interaction of lead compounds with HERG potassium channels, which is one of the primary known causes of VT induction, is an obligatory test during drug development. However, experimental and clinical data support the hypothesis that the inhibition of ion channels is not the only mechanism of VT induction. Therefore, the identification of other drug targets contributing to the induction of VT is crucial. We developed a systems chemical biology approach for searching for such targets. This approach involves the following steps: (1) creation of special sets of VT-causing and non-VT-causing drugs, (2) statistical analysis of in silico predicted drug-target interaction profiles of studied drugs with 1738 human protein targets for the identification of potential VT-related targets, (3) gene ontology and pathway enrichment analysis of the revealed targets for the identification of biological processes underlying drug-induced VT etiology, (4) creation of a cardiomyocyte regulatory network (CRN) based on general and heart-specific signaling and regulatory pathways, and (5) simulation of changes in the behavior of the CRN caused by the inhibition of each node for the identification of potential VT-related targets. As a result...
Carbon nanotubes represent ideal probes for high-resolution structural and chemical imaging of biomolecules with atomic force microscopy. Recent advances in fabrication of carbon nanotube probes with sub-nanometer radii promise to yield unique insights into the structure, dynamics and function of biological macromolecules and complexes.; Chemistry and Chemical Biology
Raman signals from molecules adsorbed on a noble metal surface are enhanced by many orders of magnitude due to the plasmon resonances of the substrate. Additionally, the enhanced spectra are modified compared to the spectra of neat molecules; many vibrational frequencies are shifted, and relative intensities undergo significant changes upon attachment to the metal. With the goal of devising an effective scheme for separating the electromagnetic and chemical effects, we explore the origin of the Raman spectra modification of benzenethiol adsorbed on nanostructured gold surfaces. The spectral modifications are attributed to the frequency dependence of the electromagnetic enhancement and to the effect of chemical binding. The latter contribution can be reproduced computationally using molecule−metal cluster models. We present evidence that the effect of chemical binding is mostly due to changes in the electronic structure of the molecule rather than to the fixed orientation of molecules relative to the substrate.; Chemistry and Chemical Biology; Engineering and Applied Sciences
This Review discusses the potential usefulness of the worm Caenorhabditis elegans as a model organism for chemists interested in studying living systems. C. elegans, a 1 mm long roundworm, is a popular model organism in almost all areas of modern biology. The worm has several features that make it attractive for biology: it is small (<1000 cells), transparent, and genetically tractable. Despite its simplicity, the worm exhibits complex phenotypes associated with multicellularity: the worm has differentiated cells and organs, it ages and has a well-defined lifespan, and it is capable of learning and remembering. This Review argues that the balance between simplicity and complexity in the worm will make it a useful tool in determining the relationship between molecular-scale phenomena and organism-level phenomena, such as aging, behavior, cognition, and disease. Following an introduction to worm biology, the Review provides examples of current research with C. elegans that is chemically relevant. It also describes tools—biological, chemical, and physical—that are available to researchers studying the worm.; Chemistry and Chemical Biology
Recently there has been an explosion of new data sources about genes, proteins, genetic variations, chemical compounds, diseases and drugs. Integration of these data sources and the identification of patterns that go across them is of critical interest. Initiatives such as Bio2RDF and LODD have tackled the problem of linking biological data and drug data respectively using RDF. Thus far, the inclusion of chemogenomic and systems chemical biology information that crosses the domains of chemistry and biology has been very limited.
We have created a single repository called Chem2Bio2RDF by aggregating data from multiple chemogenomics repositories that is cross-linked into Bio2RDF and LODD. We have also created a linked-path generation tool to facilitate SPARQL query generation, and have created extended SPARQL functions to address specific chemical/biological search needs. We demonstrate the utility of Chem2Bio2RDF in investigating polypharmacology, identification of potential multiple pathway inhibitors, and the association of pathways with adverse drug reactions.
We have created a new semantic systems chemical biology resource, and have demonstrated its potential usefulness in specific examples of polypharmacology...
Ding, Ying; Zhu, Qian; Wang, Huijun; Jiao, Dazhi; Dong, Xiao; Chen, Bin; Wild, David J.
Fonte: BioMed CentralPublicador: BioMed Central
Tipo: Artigo de Revista Científica
Relevância na Pesquisa
Background: Recently there has been an explosion of new data sources about genes, proteins, genetic variations,
chemical compounds, diseases and drugs. Integration of these data sources and the identification of patterns that go
across them is of critical interest. Initiatives such as Bio2RDF and LODD have tackled the problem of linking biological
data and drug data respectively using RDF. Thus far, the inclusion of chemogenomic and systems chemical biology
information that crosses the domains of chemistry and biology has been very limited
Results: We have created a single repository called Chem2Bio2RDF by aggregating data from multiple
chemogenomics repositories that is cross-linked into Bio2RDF and LODD. We have also created a linked-path
generation tool to facilitate SPARQL query generation, and have created extended SPARQL functions to address
specific chemical/biological search needs. We demonstrate the utility of Chem2Bio2RDF in investigating
polypharmacology, identification of potential multiple pathway inhibitors, and the association of pathways with
adverse drug reactions.
Conclusions: We have created a new semantic systems chemical biology resource, and have demonstrated its
potential usefulness in specific examples of polypharmacology...
Fonte: Chemistry Central Ltd.Publicador: Chemistry Central Ltd.
Tipo: Artigo de Revista Científica
Relevância na Pesquisa
Background: Systems chemical biology and chemogenomics are considered critical, integrative disciplines in modern biomedical research, but require data mining of large, integrated, heterogeneous datasets from chemistry and biology. We previously developed an RDF-based resource called Chem2Bio2RDF that enabled querying of such data using the SPARQL query language. Whilst this work has proved useful in its own right as one of the first major resources in these disciplines, its utility could be greatly improved by the application of an ontology for annotation of the nodes and edges in the RDF graph, enabling a much richer range of semantic queries to be issued.
Results: We developed a generalized chemogenomics and systems chemical biology OWL ontology called Chem2Bio2OWL that describes the semantics of chemical compounds, drugs, protein targets, pathways, genes, diseases and side-effects, and the relationships between them. The ontology also includes data provenance. We used it to annotate our Chem2Bio2RDF dataset, making it a rich semantic resource. Through a series of scientific case studies we demonstrate how this (i) simplifies the process of building SPARQL queries, (ii) enables useful new kinds of queries on the data and (iii) makes possible intelligent reasoning and semantic graph mining in chemogenomics and systems chemical biology.
Availability: Chem2Bio2OWL is available at http://chem2bio2rdf.org/owl. The document is available at http:// chem2bio2owl.wikispaces.com.
The involvement of free radicals in life sciences has constantly increased with time and has been connected to several physiological and pathological processes. This subject embraces diverse scientific areas, spanning from physical, biological and bioorganic chemistry to biology and medicine, with applications to the amelioration of quality of life, health and aging. Multidisciplinary skills are required for the full investigation of the many facets of radical processes in the biological environment and chemical knowledge plays a crucial role in unveiling basic processes and mechanisms. We developed a chemical biology approach able to connect free radical chemical reactivity with biological processes, providing information on the mechanistic pathways and products. The core of this approach is the design of biomimetic models to study biomolecule behavior (lipids, nucleic acids and proteins) in aqueous systems, obtaining insights of the reaction pathways as well as building up molecular libraries of the free radical reaction products. This context can be successfully used for biomarker discovery and examples are provided with two classes of compounds: mono-trans isomers of cholesteryl esters, which are synthesized and used as references for detection in human plasma...
The Chem2Bio2RDF portal is a Linked Open Data (LOD) portal for systems
chemical biology aiming for facilitating drug discovery. It converts around 25
different datasets on genes, compounds, drugs, pathways, side effects,
diseases, and MEDLINE/PubMed documents into RDF triples and links them to other
LOD bubbles, such as Bio2RDF, LODD and DBPedia. The portal is based on D2R
server and provides a SPARQL endpoint, but adds on few unique features like RDF
faceted browser, user-friendly SPARQL query generator, MEDLINE/PubMed cross
validation service, and Cytoscape visualization plugin. Three use cases
demonstrate the functionality and usability of this portal.; Comment: 8 pages, 10 figures
Building circuits and studying their behavior in cells is a major goal of
systems and synthetic biology. Synthetic biology enables the precise control of
cellular states for systems studies, the discovery of novel parts, control
strategies, and interactions for the design of robust synthetic systems. To the
best of our knowledge,there are no literature reports for the synthetic circuit
construction for protozoan parasites. This paper describes the construction of
genetic circuit for the targeted enzyme inositol phosphorylceramide synthase
belonging to the protozoan parasite Leishmania. To explore the dynamic nature
of the circuit designed, simulation was done followed by circuit validation by
qualitative and quantitative approaches. The genetic circuit designed for
inositol phosphorylceramide synthase shows responsiveness, oscillatory and
bistable behavior, together with intrinsic robustness.; Comment: This is Master of Science thesis from Sardar Patel university. Part
of the thesis has been published as the following paper: "Mandlik, Vineetha,
Dixita Limbachiya, Sonali Shinde, Milsee Mol, and Shailza Singh. "Synthetic
circuit of inositol phosphorylceramide synthase in Leishmania: a chemical
biology approach." Journal of Chemical Biology (2012): 1-12" in the Journal
of Chemical Biology
Chemical biology approach enables us to understand the complex biological systems, using small molecules such as a specific activator or inhibitor of protein, a hormone-like inducer, or a neurotransmitter. When such approach is performed genome-widely, that research is especially called "chemical genomics". We are planning to make a new start of chemical genomics using one of chordate model animal, ascidian. As a first step, we constructed a database called ACBD (Ascidians Chemical Biology Database).
First, we reviewed and annotated past articles which describe the uses of small chemicals in the field of ascidians biology. In ACBD, chemical information and effects on ascidian are manually extracted from more than 900 articles in PubMed database from 1964 to 2010. ACBD is free and open to the public on the web. ACBD has two main parts. One part consists of information about already-used chemicals to ascidians. This part is based on the record of already-published articles. In this part, we realized that more than 351 kinds of chemicals were applied for ascidian and that more than 399 kinds of chemicals were isolated from 120 kinds of tunicates!
The other part consists of “not-yet-used chemicals” information. Although the total number of Ciona protein model (KH model...
Chemical biology approach enables us to understand the complex biological systems,using small molecules such as a specific activator or inhibitor of protein, a hormone-likeinducer, or a neurotransmitter etc. When such approach is performed genome-widely, that research is especially called "chemical genomics". We are planning to make a new start of chemical genomics using one of chordate model animal, ascidian. As a first step, we constructed a database called ACBD (Ascidians Chemical Biology Database).
First, we reviewed and annotated past articles which describe the uses of small chemicals in the field of ascidians biology. In ACBD, chemical information and effects on ascidian are manually extracted from more than 900 articles in PubMed database since 1964. ACBD is free and open to the public on the web. ACBD consists of two main parts. One part consists of information about already-used chemicals to ascidians. This part is based on the record of already-published articles. In this part, we realized that more than 351 kinds of chemicals were applied for ascidian and that more than 399 kinds of chemicals were isolated from
120 kinds of tunicates.
The other part consists of "not-yet-used chemicals" information. Although the total number of Ciona protein model (KH model...