scholarly journals The IUPHAR/BPS Guide to PHARMACOLOGY in 2020: extending immunopharmacology content and introducing the IUPHAR/MMV Guide to MALARIA PHARMACOLOGY

2019 ◽  
Author(s):  
Jane F Armstrong ◽  
Elena Faccenda ◽  
Simon D Harding ◽  
Adam J Pawson ◽  
Christopher Southan ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Open Access ◽  
Molecular Interactions ◽  
Malaria Parasite ◽  
Antimalarial Activity ◽  
Molecular Targets ◽  
Interaction Data ◽  
Data Types ◽  
Global Challenge ◽  
Screening Assays

Abstract The IUPHAR/BPS Guide to PHARMACOLOGY (www.guidetopharmacology.org) is an open-access, expert-curated database of molecular interactions between ligands and their targets. We describe significant updates made over the seven releases during the last two years. The database is notably enhanced through the continued linking of relevant pharmacology with key immunological data types as part of the IUPHAR Guide to IMMUNOPHARMACOLOGY (www.guidetoimmunopharmacology.org) and by a major new extension, the IUPHAR/MMV Guide to Malaria PHARMACOLOGY (www.guidetomalariapharmacology.org). The latter has been constructed in partnership with the Medicines for Malaria Venture, an organization dedicated to identifying, developing and delivering new antimalarial therapies that are both effective and affordable. This is in response to the global challenge of over 200 million cases of malaria and 400 000 deaths worldwide, with the majority in the WHO Africa Region. It provides new pharmacological content, including molecular targets in the malaria parasite, interaction data for ligands with antimalarial activity, and establishes curation of data from screening assays, used routinely in antimalarial drug discovery, against the whole organism. A dedicated portal has been developed to provide quick and focused access to these new data.

Current Approaches to Drug Discovery for Chagas Disease: Methodological Advances

2019 ◽  
Vol 22 (8) ◽  
pp. 509-520
Author(s):  
Cauê B. Scarim ◽  
Chung M. Chin
Keyword(s):  
Drug Discovery ◽  
Chagas Disease ◽  
Drug Candidates ◽  
Lead Compounds ◽  
New Drug ◽  
Compound Libraries ◽  
Screening Assays ◽  
Cruzi Infection

Background: In recent years, there has been an improvement in the in vitro and in vivo methodology for the screening of anti-chagasic compounds. Millions of compounds can now have their activity evaluated (in large compound libraries) by means of high throughput in vitro screening assays. Objective: Current approaches to drug discovery for Chagas disease. Method: This review article examines the contribution of these methodological advances in medicinal chemistry in the last four years, focusing on Trypanosoma cruzi infection, obtained from the PubMed, Web of Science, and Scopus databases. Results: Here, we have shown that the promise is increasing each year for more lead compounds for the development of a new drug against Chagas disease. Conclusion: There is increased optimism among those working with the objective to find new drug candidates for optimal treatments against Chagas disease.

Role of Cytochrome P450 in Prostate Cancer and its Therapy

2020 ◽  
Vol 16 (1) ◽  
pp. 63-73 ◽  
Author(s):  
Rishabh Kaushik ◽  
Sheeza Khan ◽  
Meesha Sharma ◽  
Srinivasan Hemalatha ◽  
Zeba Mueed ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cytochrome P450 ◽  
Drug Discovery ◽  
Cholesterol Metabolism ◽  
Molecular Targets ◽  
Health Concern ◽  
Metabolic Functions ◽  
Novel Drugs ◽  
Genes Encoding ◽  
Causes Of Mortality

Prostate cancer has become a global health concern as it is one of the leading causes of mortality in males. With the emerging drug resistance to conventional therapies, it is imperative to unravel new molecular targets for disease prevention. Cytochrome P450 (P450s or CYPs) represents a unique class of mixed-function oxidases which catalyses a wide array of biosynthetic and metabolic functions including steroidogenesis and cholesterol metabolism. Several studies have reported the overexpression of the genes encoding CYPs in prostate cancer cells and how they can be used as molecular targets for drug discovery. But due to functional redundancy and overlapping expression of CYPs in several other metabolic pathways there are several impediments in the clinical efficacy of the novel drugs reported till now. Here we review the most crucial P450 enzymes which are involved in prostate cancer and how they can be used as molecular targets for drug discovery along with the clinical limitations of the currently existing CYP inhibitors.

scholarly journals Integrating High-Content Analysis into a Multiplexed Screening Approach to Identify and Characterize GPCR Agonists

2014 ◽  
Vol 19 (7) ◽  
pp. 1079-1089 ◽  
Author(s):  
Yingjie Zhu ◽  
John Watson ◽  
Mengjie Chen ◽  
Ding Ren Shen ◽  
Melissa Yarde ◽  
...  
Keyword(s):  
Drug Discovery ◽  
G Protein Coupled Receptors ◽  
High Content Imaging ◽  
Biased Agonism ◽  
Receptor Oligomerization ◽  
Sphingosine 1 Phosphate ◽  
High Content Analysis ◽  
Screening Assays ◽  
Hit Identification ◽  
G Protein Coupled

G protein–coupled receptors (GPCRs) are one of the most popular and proven target classes for therapeutic intervention. The increased appreciation for allosteric modulation, receptor oligomerization, and biased agonism has led to the development of new assay platforms that seek to capitalize on these aspects of GPCR biology. High-content screening is particularly well suited for GPCR drug discovery given the ability to image and quantify changes in multiple cellular parameters, to resolve subcellular structures, and to monitor events within a physiologically relevant environment. Focusing on the sphingosine-1-phosphate (S1P1) receptor, we evaluated the utility of high-content approaches in hit identification efforts by developing and applying assays to monitor β-arrestin translocation, GPCR internalization, and GPCR recycling kinetics. Using these approaches in combination with more traditional GPCR screening assays, we identified compounds whose unique pharmacological profiles would have gone unnoticed if using a single platform. In addition, we identified a compound that induces an atypical pattern of β-arrestin translocation and GPCR recycling kinetics. Our results highlight the value of high-content imaging in GPCR drug discovery efforts and emphasize the value of a multiassay approach to study pharmacological properties of compounds of interest.

scholarly journals An Open-Access Platform for Translating Diabetes and Cardiometabolic Disease Genetics Into Accessible Knowledge

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A406-A406
Author(s):  
Maria Costanzo ◽  
Kenneth Bruskiewicz ◽  
Lizz Caulkins ◽  
Marc Duby ◽  
Clint Gilbert ◽  
...  
Keyword(s):  
Open Access ◽  
Cardiometabolic Disease ◽  
Common Disease ◽  
Genome Wide Association Studies ◽  
Functional Genomic ◽  
Genetic Associations ◽  
Data Types ◽  
Bottom Line ◽  
Tissue Specific ◽  
Effector Genes

Abstract Most associations from genome-wide association studies (GWAS) result from as-yet-unknown alterations of molecular or cellular function; the causal variants and effector genes responsible for them, and the tissues and pathways through which they act, remain largely unknown. Thousands of associated loci have now been identified for each common disease and its related traits. In order to translate GWAS data into biological knowledge, they must be integrated with functional genomic annotations reflecting tissue-specific regulation and with the results of bioinformatic methods that predict the functional effects of associations. However, these data types are typically spread across disparate resources, and working with them requires bioinformatic expertise. To make these results accessible and understandable to the broader diabetes and cardiometabolic disease research communities, we have developed the open-access Common Metabolic Diseases Knowledge Portal (CMDKP; cmdkp.org), which brings together a robust software and data storage platform with a streamlined and intuitive user interface for four disease areas: diabetes (both types 1 and 2); cardiovascular disease; cerebrovascular disease; and sleep and circadian disorders. The CMDKP enables researchers to access and explore a comprehensive matrix of genetic, genomic, and computational results. It includes 3 classes of genomic data: 1) GWAS summary statistics from the most current and authoritative datasets available, as identified by disease-area experts; 2) functional genomic annotations, such as chromatin accessibility, that reflect the tissue-specific regulatory potential of genomic regions; and 3) the results of bioinformatic methods applied to these aggregated data (for example, overlap-aware meta-analysis to determine “bottom-line” p-values, the GREGOR method for determining tissue-specific enrichment of genetic associations, the MAGMA method for generating gene-level association scores, and more). All of these data types are integrated and accessible via interactive tools that allow researchers to explore and evaluate the data in order to identify candidate disease effector genes for further research. The CMDKP provides researchers with the data and tools necessary to translate genetic associations and functional annotations into knowledge about disease mechanisms and potential therapeutic targets.

scholarly journals A New Big-Data Paradigm for Target Identification and Drug Discovery

2017 ◽  
Author(s):  
Neel S. Madhukar ◽  
Prashant K. Khade ◽  
Linda Huang ◽  
Kaitlyn Gayvert ◽  
Giuseppe Galletti ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Small Molecules ◽  
Clinical Application ◽  
Small Molecule ◽  
Target Identification ◽  
Clinical Development ◽  
Data Types ◽  
Public Data ◽  
Drug Target Identification ◽  
Approved Drugs

AbstractDrug target identification is one of the most important aspects of pre-clinical development yet it is also among the most complex, labor-intensive, and costly. This represents a major issue, as lack of proper target identification can be detrimental in determining the clinical application of a bioactive small molecule. To improve target identification, we developed BANDIT, a novel paradigm that integrates multiple data types within a Bayesian machine-learning framework to predict the targets and mechanisms for small molecules with unprecedented accuracy and versatility. Using only public data BANDIT achieved an accuracy of approximately 90% over 2000 different small molecules – substantially better than any other published target identification platform. We applied BANDIT to a library of small molecules with no known targets and generated ∼4,000 novel molecule-target predictions. From this set we identified and experimentally validated a set of novel microtubule inhibitors, including three with activity on cancer cells resistant to clinically used anti-microtubule therapies. We next applied BANDIT to ONC201 – an active anti- cancer small molecule in clinical development – whose target has remained elusive since its discovery in 2009. BANDIT identified dopamine receptor 2 as the unexpected target of ONC201, a prediction that we experimentally validated. Not only does this open the door for clinical trials focused on target-based selection of patient populations, but it also represents a novel way to target GPCRs in cancer. Additionally, BANDIT identified previously undocumented connections between approved drugs with disparate indications, shedding light onto previously unexplained clinical observations and suggesting new uses of marketed drugs. Overall, BANDIT represents an efficient and highly accurate platform that can be used as a resource to accelerate drug discovery and direct the clinical application of small molecule therapeutics with improved precision.

scholarly journals Screen of traditional soup broths with reported antipyretic activity towards the discovery of potential antimalarials

2019 ◽  
Vol 104 (12) ◽  
pp. 1138-1142 ◽  
Author(s):  
◽  
Ursula Straschil ◽  
Kathrin Witmer ◽  
Michael J Delves ◽  
Stephen D Marks ◽  
...  
Keyword(s):  
Malaria Parasite ◽  
Antimalarial Activity ◽  
Ethnic Origin ◽  
Double Blind Study ◽  
Sexual Stage ◽  
Double Blind ◽  
Antipyretic Activity ◽  
Natural Remedies ◽  
Stage Development

ObjectiveThe global impact of artemisinin-based combination therapies on malaria-associated mortality and their origins in ancient Chinese medicine has heightened interest in the natural discovery of future antimalarials.MethodsA double-blind study to identify potential ingredients with antimalarial activity from traditional remedies with reported antipyretic properties. Recipes of clear broths, passed down by tradition in families of diverse ethnic origin, were sourced by school children. Broths were then tested for their ability to arrest malaria parasite asexual growth or sexual stage development in vitro. Clear broth extract was incubated with in vitro cultures of Plasmodium falciparum asexual or mature sexual stage cultures and assayed for parasite viability after 72 hours.ResultsOf the 56 broths tested, 5 were found to give >50% in vitro growth inhibition against P. falciparum asexual blood stages, with 2 having comparable inhibition to that seen with dihydroartemisinin, a leading antimalarial. Four other broths were found to have >50% transmission blocking activity, preventing male parasite sexual stage development. After unblinding, two active broths were found to be from siblings from different classes, who had brought in the same vegetarian soup, demonstrating assay robustness.ConclusionsThis screening approach succeeded in finding broths with activity against malaria parasite in vitro growth, arising from complex vegetable and/or meat-based broths. This represented a successful child education exercise, in teaching about the interface between natural remedies, traditional medicine and evidence-based drug discovery.

scholarly journals Drug Discovery for Chagas Disease: Impact of Different Host Cell Lines on Assay Performance and Hit Compound Selection

2019 ◽  
Vol 4 (2) ◽  
pp. 82 ◽  
Author(s):  
Caio Haddad Franco ◽  
Laura Maria Alcântara ◽  
Eric Chatelain ◽  
Lucio Freitas-Junior ◽  
Carolina Borsoi Moraes
Keyword(s):  
Drug Discovery ◽  
Host Cell ◽  
Cell Lines ◽  
Chagas Disease ◽  
Host Cells ◽  
Mammalian Cell Lines ◽  
Starting Point ◽  
Disease Impact ◽  
Screening Assays ◽  
Host Parasite

Cell-based screening has become the major compound interrogation strategy in Chagas disease drug discovery. Several different cell lines have been deployed as host cells in screening assays. However, host cell characteristics and host-parasite interactions may play an important role when assessing anti-T. cruzi compound activity, ultimately impacting on hit discovery. To verify this hypothesis, four distinct mammalian cell lines (U2OS, THP-1, Vero and L6) were used as T. cruzi host cells in High Content Screening assays. Rates of infection varied greatly between different host cells. Susceptibility to benznidazole also varied, depending on the host cell and parasite strain. A library of 1,280 compounds was screened against the four different cell lines infected with T. cruzi, resulting in the selection of a total of 82 distinct compounds as hits. From these, only two hits were common to all four cell lines assays (2.4%) and 51 were exclusively selected from a single assay (62.2%). Infected U2OS cells were the most sensitive assay, as 55 compounds in total were identified as hits; infected THP-1 yielded the lowest hit rates, with only 16 hit compounds. Of the selected hits, compound FPL64176 presented selective anti-T. cruzi activity and could serve as a starting point for the discovery of new anti-chagasic drugs.

Open-access liquid chromatography/mass spectrometry in a drug discovery environment

2002 ◽  
Vol 37 (9) ◽  
pp. 889-896 ◽  
Author(s):  
Larry M. Mallis ◽  
Ani B. Sarkahian ◽  
John M. Kulishoff ◽  
William L. Watts
Keyword(s):  
Mass Spectrometry ◽  
Liquid Chromatography ◽  
Drug Discovery ◽  
Open Access ◽  
Liquid Chromatography Mass Spectrometry ◽  
Chromatography Mass Spectrometry
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