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Essays in Biochemistry

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https://www.readbyqxmd.com/read/28986384/mass-spectrometry-for-fragment-screening
#1
REVIEW
Daniel Shiu-Hin Chan, Andrew J Whitehouse, Anthony G Coyne, Chris Abell
Fragment-based approaches in chemical biology and drug discovery have been widely adopted worldwide in both academia and industry. Fragment hits tend to interact weakly with their targets, necessitating the use of sensitive biophysical techniques to detect their binding. Common fragment screening techniques include differential scanning fluorimetry (DSF) and ligand-observed NMR. Validation and characterization of hits is usually performed using a combination of protein-observed NMR, isothermal titration calorimetry (ITC) and X-ray crystallography...
October 6, 2017: Essays in Biochemistry
https://www.readbyqxmd.com/read/28970340/protein-degradation-a-validated-therapeutic-strategy-with-exciting-prospects
#2
REVIEW
Honorine Lebraud, Tom D Heightman
In a time of unprecedented challenges in developing potent, selective and well-tolerated protein inhibitors as therapeutics, drug hunters are increasingly seeking alternative modalities to modulate pharmacological targets. Selective inhibitors are achievable for only a fraction of the proteome, and are not guaranteed to elicit the desired response in patients, especially when pursuing targets identified through genetic knockdown. Targeted protein degradation holds the potential to expand the range of proteins that can be effectively modulated...
October 2, 2017: Essays in Biochemistry
https://www.readbyqxmd.com/read/28951470/essential-chemistry-for-biochemists
#3
REVIEW
Amanda L Jonsson, Mark A J Roberts, J L Kiappes, Kathryn A Scott
Within every living organism, countless reactions occur every second. These reactions typically occur more rapidly and with greater efficiency than would be possible under the same conditions in the chemical laboratory, and while using only the subset of elements that are readily available in nature. Despite these apparent differences between life and the laboratory, biological reactions are governed by the same rules as any other chemical reaction. Thus, a firm understanding of the fundamentals of chemistry is invaluable in biochemistry...
September 26, 2017: Essays in Biochemistry
https://www.readbyqxmd.com/read/29118099/the-potential-of-cryo-electron-microscopy-for-structure-based-drug-design
#4
REVIEW
Andreas Boland, Leifu Chang, David Barford
Structure-based drug design plays a central role in therapeutic development. Until recently, protein crystallography and NMR have dominated experimental approaches to obtain structural information of biological molecules. However, in recent years rapid technical developments in single particle cryo-electron microscopy (cryo-EM) have enabled the determination to near-atomic resolution of macromolecules ranging from large multi-subunit molecular machines to proteins as small as 64 kDa. These advances have revolutionized structural biology by hugely expanding both the range of macromolecules whose structures can be determined, and by providing a description of macromolecular dynamics...
November 8, 2017: Essays in Biochemistry
https://www.readbyqxmd.com/read/29118098/x-ray-free-electron-laser-opportunities-for-drug-discovery
#5
REVIEW
Robert K Y Cheng, Rafael Abela, Michael Hennig
Past decades have shown the impact of structural information derived from complexes of drug candidates with their protein targets to facilitate the discovery of safe and effective medicines. Despite recent developments in single particle cryo-electron microscopy, X-ray crystallography has been the main method to derive structural information. The unique properties of X-ray free electron laser (XFEL) with unmet peak brilliance and beam focus allow X-ray diffraction data recording and successful structure determination from smaller and weaker diffracting crystals shortening timelines in crystal optimization...
November 8, 2017: Essays in Biochemistry
https://www.readbyqxmd.com/read/29118097/molecular-recognition-of-ternary-complexes-a-new-dimension-in-the-structure-guided-design-of-chemical-degraders
#6
REVIEW
Scott J Hughes, Alessio Ciulli
Molecular glues and bivalent inducers of protein degradation (also known as PROTACs) represent a fascinating new modality in pharmacotherapeutics: the potential to knockdown previously thought 'undruggable' targets at sub-stoichiometric concentrations in ways not possible using conventional inhibitors. Mounting evidence suggests these chemical agents, in concert with their target proteins, can be modelled as three-body binding equilibria that can exhibit significant cooperativity as a result of specific ligand-induced molecular recognition...
November 8, 2017: Essays in Biochemistry
https://www.readbyqxmd.com/read/29118096/the-sgc-beyond-structural-genomics-redefining-the-role-of-3d-structures-by-coupling-genomic-stratification-with-fragment-based-discovery
#7
REVIEW
Anthony R Bradley, Aude Echalier, Michael Fairhead, Claire Strain-Damerell, Paul Brennan, Alex N Bullock, Nicola A Burgess-Brown, Elisabeth P Carpenter, Opher Gileadi, Brian D Marsden, Wen Hwa Lee, Wyatt Yue, Chas Bountra, Frank von Delft
The ongoing explosion in genomics data has long since outpaced the capacity of conventional biochemical methodology to verify the large number of hypotheses that emerge from the analysis of such data. In contrast, it is still a gold-standard for early phenotypic validation towards small-molecule drug discovery to use probe molecules (or tool compounds), notwithstanding the difficulty and cost of generating them. Rational structure-based approaches to ligand discovery have long promised the efficiencies needed to close this divergence; in practice, however, this promise remains largely unfulfilled, for a host of well-rehearsed reasons and despite the huge technical advances spearheaded by the structural genomics initiatives of the noughties...
November 8, 2017: Essays in Biochemistry
https://www.readbyqxmd.com/read/29118095/nmr-in-structure-based-drug-design
#8
REVIEW
Marta G Carneiro, Eiso Ab, Stephan Theisgen, Gregg Siegal
NMR spectroscopy is a powerful technique that can provide valuable structural information for drug discovery endeavors. Here, we discuss the strengths (and limitations) of NMR applications to structure-based drug discovery, highlighting the different levels of resolution and throughput obtainable. Additionally, the emerging field of paramagnetic NMR in drug discovery and recent developments in approaches to speed up and automate protein-observed NMR data collection and analysis are discussed.
November 8, 2017: Essays in Biochemistry
https://www.readbyqxmd.com/read/29118094/fragment-based-drug-discovery-and-its-application-to-challenging-drug-targets
#9
REVIEW
Amanda J Price, Steven Howard, Benjamin D Cons
Fragment-based drug discovery (FBDD) is a technique for identifying low molecular weight chemical starting points for drug discovery. Since its inception 20 years ago, FBDD has grown in popularity to the point where it is now an established technique in industry and academia. The approach involves the biophysical screening of proteins against collections of low molecular weight compounds (fragments). Although fragments bind to proteins with relatively low affinity, they form efficient, high quality binding interactions with the protein architecture as they have to overcome a significant entropy barrier to bind...
November 8, 2017: Essays in Biochemistry
https://www.readbyqxmd.com/read/29118093/current-perspectives-in-fragment-based-lead-discovery-fbld
#10
REVIEW
Bas Lamoree, Roderick E Hubbard
It is over 20 years since the first fragment-based discovery projects were disclosed. The methods are now mature for most 'conventional' targets in drug discovery such as enzymes (kinases and proteases) but there has also been growing success on more challenging targets, such as disruption of protein-protein interactions. The main application is to identify tractable chemical startpoints that non-covalently modulate the activity of a biological molecule. In this essay, we overview current practice in the methods and discuss how they have had an impact in lead discovery - generating a large number of fragment-derived compounds that are in clinical trials and two medicines treating patients...
November 8, 2017: Essays in Biochemistry
https://www.readbyqxmd.com/read/29118092/structure-based-discovery-of-cyclin-dependent-protein-kinase-inhibitors
#11
REVIEW
Mathew P Martin, Jane A Endicott, Martin E M Noble
The cell fate-determining roles played by members of the cyclin-dependent protein kinase (CDK) family explain why their dysregulation can promote proliferative diseases, and identify them as potential targets for drug discovery in oncology and beyond. After many years of research, the first efficacious CDK inhibitors have now been registered for clinical use in a defined segment of breast cancer. Research is underway to identify inhibitors with appropriate CDK-inhibitory profiles to recapitulate this success in other disease settings...
November 8, 2017: Essays in Biochemistry
https://www.readbyqxmd.com/read/29118091/structure-based-drug-design-aiming-for-a-perfect-fit
#12
REVIEW
Rob L M van Montfort, Paul Workman
Knowledge of the three-dimensional structure of therapeutically relevant targets has informed drug discovery since the first protein structures were determined using X-ray crystallography in the 1950s and 1960s. In this editorial we provide a brief overview of the powerful impact of structure-based drug design (SBDD), which has its roots in computational and structural biology, with major contributions from both academia and industry. We describe advances in the application of SBDD for integral membrane protein targets that have traditionally proved very challenging...
November 8, 2017: Essays in Biochemistry
https://www.readbyqxmd.com/read/29089380/correction-photosynthesis
#13
Matthew P Johnson
No abstract text is available yet for this article.
October 31, 2017: Essays in Biochemistry
https://www.readbyqxmd.com/read/28887328/experimental-evolution-in-photoautotrophic-microorganisms-as-a-means-of-enhancing-chloroplast-functions
#14
REVIEW
Dario Leister
The term 'experimental evolution' refers to short-term evolutionary experiments with microorganisms under controlled conditions in which selection is expected to occur. In combination with whole-genome sequencing and genetic engineering, the method has become a powerful tool to study evolutionary mechanisms and engineer new microbial variants. It has been most extensively used in the model species Escherichia coli and Saccharomyces cerevisiae, but more recently photosynthetic microorganisms have been subjected to experimental evolution...
September 7, 2017: Essays in Biochemistry
https://www.readbyqxmd.com/read/28698312/approaches-for-extending-human-healthspan-from-antioxidants-to-healthspan-pharmacology
#15
REVIEW
Jan Gruber, Barry Halliwell
Dramatic increases in human lifespan and declining population growth are monumental achievements but these same achievements have also led to many societies today ageing at a faster rate than ever before. Extending healthy lifespan (healthspan) is a key translational challenge in this context. Disease-centric approaches to manage population ageing risk are adding years to life without adding health to these years. The growing consensus that ageing is driven by a limited number of interconnected processes suggests an alternative approach...
July 15, 2017: Essays in Biochemistry
https://www.readbyqxmd.com/read/28698311/proteomics-and-metabolomics-in-ageing-research-from-biomarkers-to-systems-biology
#16
REVIEW
Jessica M Hoffman, Yang Lyu, Scott D Pletcher, Daniel E L Promislow
Age is the single greatest risk factor for a wide range of diseases, and as the mean age of human populations grows steadily older, the impact of this risk factor grows as well. Laboratory studies on the basic biology of ageing have shed light on numerous genetic pathways that have strong effects on lifespan. However, we still do not know the degree to which the pathways that affect ageing in the lab also influence variation in rates of ageing and age-related disease in human populations. Similarly, despite considerable effort, we have yet to identify reliable and reproducible 'biomarkers', which are predictors of one's biological as opposed to chronological age...
July 15, 2017: Essays in Biochemistry
https://www.readbyqxmd.com/read/28698310/systems-modelling-ageing-from-single-senescent-cells-to-simple-multi-cellular-models
#17
REVIEW
Alvaro Martinez Guimera, Ciaran Welsh, Piero Dalle Pezze, Nicola Fullard, Glyn Nelson, Mathilde F Roger, Stefan A Przyborski, Daryl P Shanley
Systems modelling has been successfully used to investigate several key molecular mechanisms of ageing. Modelling frameworks to allow integration of models and methods to enhance confidence in models are now well established. In this article, we discuss these issues and work through the process of building an integrated model for cellular senescence as a single cell and in a simple tissue context.
July 15, 2017: Essays in Biochemistry
https://www.readbyqxmd.com/read/28698309/differential-control-of-ageing-and-lifespan-by-isoforms-and-splice-variants-across-the-mtor-network
#18
REVIEW
Patricia Razquin Navas, Kathrin Thedieck
Ageing can be defined as the gradual deterioration of physiological functions, increasing the incidence of age-related disorders and the probability of death. Therefore, the term ageing not only reflects the lifespan of an organism but also refers to progressive functional impairment and disease. The nutrient-sensing kinase mTOR (mammalian target of rapamycin) is a major determinant of ageing. mTOR promotes cell growth and controls central metabolic pathways including protein biosynthesis, autophagy and glucose and lipid homoeostasis...
July 15, 2017: Essays in Biochemistry
https://www.readbyqxmd.com/read/28698308/the-role-of-attenuated-redox-and-heat-shock-protein-responses-in-the-age-related-decline-in-skeletal-muscle-mass-and-function
#19
REVIEW
Anne McArdle, Malcolm J Jackson
The loss of muscle mass and weakness that accompanies ageing is a major contributor to physical frailty and loss of independence in older people. A failure of muscle to adapt to physiological stresses such as exercise is seen with ageing and disruption of redox regulated processes and stress responses are recognized to play important roles in theses deficits. The role of redox regulation in control of specific stress responses, including the generation of heat shock proteins (HSPs) by muscle appears to be particularly important and affected by ageing...
July 15, 2017: Essays in Biochemistry
https://www.readbyqxmd.com/read/28698307/origins-of-mtdna-mutations-in-ageing
#20
REVIEW
Karolina Szczepanowska, Aleksandra Trifunovic
MtDNA mutations are one of the hallmarks of ageing and age-related diseases. It is well established that somatic point mutations accumulate in mtDNA of multiple organs and tissues with increasing age and heteroplasmy is universal in mammals. However, the origin of these mutations remains controversial. The long-lasting hypothesis stating that mtDNA mutations emanate from oxidative damage via a self-perpetuating mechanism has been extensively challenged in recent years. Contrary to this initial ascertainment, mtDNA appears to be well protected from action of reactive oxygen species (ROS) through robust protein coating and endomitochondrial microcompartmentalization...
July 15, 2017: Essays in Biochemistry
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