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- Hauser, Alexander S, et al.
(author)
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Trends in GPCR drug discovery : new agents, targets and indications
- 2017
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In: Nature reviews. Drug discovery. - : Springer Science and Business Media LLC. - 1474-1776 .- 1474-1784. ; 16:12, s. 829-842
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Journal article (peer-reviewed)abstract
- G protein-coupled receptors (GPCRs) are the most intensively studied drug targets, mostly due to their substantial involvement in human pathophysiology and their pharmacological tractability. Here, we report an up-to-date analysis of all GPCR drugs and agents in clinical trials, which reveals current trends across molecule types, drug targets and therapeutic indications, including showing that 475 drugs (~34% of all drugs approved by the US Food and Drug Administration (FDA)) act at 108 unique GPCRs. Approximately 321 agents are currently in clinical trials, of which ~20% target 66 potentially novel GPCR targets without an approved drug, and the number of biological drugs, allosteric modulators and biased agonists has increased. The major disease indications for GPCR modulators show a shift towards diabetes, obesity and Alzheimer disease, although several central nervous system disorders are also highly represented. The 224 (56%) non-olfactory GPCRs that have not yet been explored in clinical trials have broad untapped therapeutic potential, particularly in genetic and immune system disorders. Finally, we provide an interactive online resource to analyse and infer trends in GPCR drug discovery.
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- Kreuger, Johan, et al.
(author)
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Targeting vascular and leukocyte communication in angiogenesis, inflammation and fibrosis
- 2016
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In: Nature reviews. Drug discovery. - : Springer Science and Business Media LLC. - 1474-1776 .- 1474-1784. ; 15:2, s. 125-142
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Research review (peer-reviewed)abstract
- Regulation of vascular permeability, recruitment of leukocytes from blood to tissue and angiogenesis are all processes that occur at the level of the microvasculature during both physiological and pathological conditions. The interplay between microvascular cells and leukocytes during inflammation, together with the emerging roles of leukocytes in the modulation of the angiogenic process, make leukocyte-vascular interactions prime targets for therapeutics to potentially treat a wide range of diseases, including pathological and dysfunctional vessel growth, chronic inflammation and fibrosis. In this Review, we discuss how the different cell types that are present in and around microvessels interact, cooperate and instruct each other, and in this context we highlight drug targets as well as emerging druggable processes that can be exploited to restore tissue homeostasis.
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- Oprea, Tudor I, et al.
(author)
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Unexplored therapeutic opportunities in the human genome
- 2018
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In: Nature Reviews Drug Discovery. - : Springer Science and Business Media LLC. - 1474-1776 .- 1474-1784. ; 17:5, s. 317-332
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Journal article (peer-reviewed)abstract
- A large proportion of biomedical research and the development of therapeutics is focused on a small fraction of the human genome. In a strategic effort to map the knowledge gaps around proteins encoded by the human genome and to promote the exploration of currently understudied, but potentially druggable, proteins, the US National Institutes of Health launched the Illuminating the Druggable Genome (IDG) initiative in 2014. In this article, we discuss how the systematic collection and processing of a wide array of genomic, proteomic, chemical and disease-related resource data by the IDG Knowledge Management Center have enabled the development of evidence-based criteria for tracking the target development level (TDL) of human proteins, which indicates a substantial knowledge deficit for approximately one out of three proteins in the human proteome. We then present spotlights on the TDL categories as well as key drug target classes, including G protein-coupled receptors, protein kinases and ion channels, which illustrate the nature of the unexplored opportunities for biomedical research and therapeutic development.
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- Renaud, Jean-Paul, et al.
(author)
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Biophysics in drug discovery : impact, challenges and opportunities
- 2016
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In: Nature reviews. Drug discovery. - : Springer Science and Business Media LLC. - 1474-1776 .- 1474-1784. ; 15:10, s. 679-698
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Research review (peer-reviewed)abstract
- Over the past 25 years, biophysical technologies such as X-ray crystallography, nuclear magnetic resonance spectroscopy, surface plasmon resonance spectroscopy and isothermal titration calorimetry have become key components of drug discovery platforms in many pharmaceutical companies and academic laboratories. There have been great improvements in the speed, sensitivity and range of possible measurements, providing high-resolution mechanistic, kinetic, thermodynamic and structural information on compound target interactions. This Review provides a framework to understand this evolution by describing the key biophysical methods, the information they can provide and the ways in which they can be applied at different stages of the drug discovery process. We also discuss the challenges for current technologies and future opportunities to use biophysical methods to solve drug discovery problems.
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