I've spent some time over the last couple of weeks updating and adding new content to the Drug Discovery Resources section of the website.
In particular, s drug targets become more challenging medicinal chemists are looking at alternatives to small molecule competitive inhibitors, the section on covalent inhibitors have been expanded and a new page on PROTACs has been added. PROTACs are bifunctional molecules that bind to the target protein and an E3 ligase, the simultaneous PROTAC binding of two proteins brings the target protein in close enough proximity for polyubiquitination by the E2 enzyme associated to the E3 ligase, which flags the target protein for degradation through the proteasome. This offers a powerful alternative to competitive inhibition.
The Probes & Drugs portal has been added to the chemical probes page, this is a public resource joining together focused libraries of bioactive compounds (probes, drugs, specific inhibitor sets etc.) with commercially available screening libraries.
The page describing commercial fragment screening libraries has been updated to include a couple of new additions and flagging some that seem to be unavailable, if I've missed any feel free to let me know.
The section on hERG has been updated with links to new references and details of hERGcentral.
hERGCentral: A Large Database to Store, Retrieve, and Analyze Compound-Human Ether-à-go-go Related Gene Channel Interactions to Facilitate Cardiotoxicity Assessment in Drug Development. The hERGCentral database hergcentral.org is based on experimental data obtained from a primary screen by electrophysiology against more than 300,000 structurally diverse compounds screened at 1 and 10uM.
Unfortunately the database appears to be no longer available. Whilst the supplementary information for the original publication does not contain the structures of the tested compounds it does reference the PubChem substance ID. I used these identifiers to download the structures of the >300,000 records and combined them with the experimental data provided in the Excel tables in the supplementary information. The complete dataset can be downloaded from the hERG page.
Small molecules can potentially bind to a variety of bimolecular targets and whilst counter-screening against a wide variety of targets is feasible it can be rather expensive and probably only realistic for when a compound has been identified as of particular interest. For this reason there is considerable interest in building computational models to predict potential interactions the page on predicting bioactivities has been expanded.
The section on bioisosteres also have a few new examples.
A publication by Fang et al DOI describes hERGCentral: A Large Database to Store, Retrieve, and Analyze Compound-Human Ether-à-go-go Related Gene Channel Interactions to Facilitate Cardiotoxicity Assessment in Drug Development. The hERGCentral database hergcentral.org is based on experimental data obtained from a primary screen by electrophysiology against more than 300,000 structurally diverse compounds screened at 1 and 10uM. Unfortunately the database appears to be no longer available. Whilst the supplementary information for the original publication does not contain the structures of the tested compounds it does reference the PubChem substance ID. I used these identifiers to download the structures of the >300,000 records and combined them with the experimental data provided in the Excel tables in the supplementary information. The complete dataset can be downloaded here in either
Bear in mind this is single point data and there will be a fair amount of scatter.
I've added this information to the page on hERG.
The Royal Society of Chemistry Medicinal Chemistry Residential School takes place 2 - 7 June 2019, Loughborough, United Kingdom is a fantastic opportunity for anyone starting out or contemplating a career in Drug Discovery.
The school is designed for graduate and post-doctoral chemists with 1-5 years’ experience in the field of drug research. Drug discovery is an interdisciplinary subject so delegates from biological or computational backgrounds will benefit from attendance at the school. In addition, final year PhD students from pharmaceutical or organic chemistry contemplating a career in drug discovery are also encouraged to attend.
The course includes the following topics:
- Target Validation
- Computational Chemistry
- Biological Mechanisms
- Pharmacokinetics and Drug Metabolism
- Screening of New Compounds
- Molecular Biology in Medicinal Chemistry
- Exploiting a Chemical Lead
- Combinatorial Chemistry and Molecular Diversity
- Case Histories of Drug Discovery
- Toxicology in Drug Discovery
- Pharmaceutical Considerations in Drug Development
- Structure-guided Drug Design
- Physical Properties and Quantitative Structure-Activity Relationships
- Hints and Tips in Medicinal Chemistry
A very interesting commentary on the impact (or lack of) genomics has had on human healthcare. J Clin Invest. 2019
The promises of precision medicine are to dramatically change patient care via individually tailored therapies and, as a result, to prevent disease, improve survival, and extend healthspan.
However, nearly two decades after the first predictions of dramatic success, we find no impact of the human genome project on the population’s life expectancy or any other public health measure, notwithstanding the vast resources that have been directed at genomics. Exaggerated expectations of how large an impact on disease would be found for genes have been paralleled by unrealistic timelines for success, yet the promotion of precision medicine continues unabated.
In light of the limitations of the precision medicine narrative, it is urgent that the biomedical research community reconsider its ongoing obsession with the human genome and reassess its research priorities including funding to more closely align with the health needs of our nation. We do not lack for pressing public health problems. We must counter the toll of obesity, inactivity, and diabetes; we need to address the mental health problems that lead to distress and violence; we cannot stand by while a terrible opiate epidemic ravages our country; we have to prepare conscientiously for the next influenza pandemic; we have a responsibility to prevent the ongoing contamination of our air, food, and water. Topics such as these have taken a back seat to the investment of the NIH and of many research universities in a human genome–driven research agenda that has done little to solve these problems, but has offered us promises and more promises.
The human genome project was undoubtedly a magnificent achievement, but has the investment in genomics delivered?
There is an extended discussion on In the Pipeline https://blogs.sciencemag.org/pipeline/archives/2019/01/31/precision-medicine-real-soon-now.
A recent publication by the World Health Organisation makes sobering reading.
The world is facing multiple health challenges. These range from outbreaks of vaccine-preventable diseases like measles and diphtheria, increasing reports of drug-resistant pathogens, growing rates of obesity and physical inactivity to the health impacts of environmental pollution and climate change and multiple humanitarian crises.
Here are 10 of the many issues that will demand attention from WHO and health partners in 2019.
- Air pollution and climate change
- Noncommunicable diseases (diabetes, cancer and heart disease)
- Global influenza pandemic
- Fragile and vulnerable settings (combination of drought, famine, conflict, and population displacement)
- Antimicrobial resistance
- Ebola and other high-threat pathogens
- Weak primary health care
- Vaccine hesitancy (the reluctance or refusal to vaccinate despite the availability of vaccine)
MMV has announced a call for drug discovery proposals
1. Compounds addressing the key priorities of the malaria eradication agenda
Novel families of molecules in the hit-to-lead or lead optimization stages are sought without G6PD deficiency liabilities that either:
Kill or reactivate hypnozoites for use as part of a P. vivax radical cure; or have activity against sexual stage V gametocytes and evidence of transmission blocking in SMFA.
2. Compounds having activity against asexual liver and/or blood stages
Novel chemical series with EC50<500nM and which have one or more of the following key features:
A known, novel mechanism of action; An inability to select resistant mutants in vitro; Activity at more than one life-cycle stage; A long half-life (ideally >4h in rodents) and confirmed in vivo efficacy. For advanced series, we are seeking novel compounds with, ideally, a predicted human half-life >100h and a predicted oral single human dose <500mg or an i.m. dose that can be administered in <1mL and sufficient for up to 3 months’ protection in humans.
3. Novel approaches for screening
To help identify new phenotypic and/ or target based hits, as well as confirm activity of MMV compounds on all human malaria asexual blood stages, new screening proposals are sought amongst the three categories below:
Validated Plasmodium target-based assays, ideally with evidence of target essentiality beyond asexual blood stages. Biological validation should be supported by a biological target based screening assay suited for identification of novel chemical series. Novel whole cell phenotypic screening paradigms to potentially identify new relevant chemistry. Asexual blood stage assays for vivax and ovale malaria.
Compounds for Target Identification
MMV also welcomes requests for support to investigate the mechanism of action of compounds:
Call for African proposals
Finally, MMV welcomes proposals from endemic region African scientists focused in the following priority areas:
Compounds with confirmed activity on any antimalarial life-cycle stage. Novel families of molecules with confirmed activity (EC50 < 10uM) and a medicinal chemistry plan that tackles any known or anticipated liability. Priority will be given to proposals that maximize use of local natural products.
Assay development and screening
In many companies/institutions/universities new arrivals are presented with a variety of desktop tools with little or no advice on how to use them other than "pick it up as you along". This workshop is intended to provide expert tutorials to get you started and show what can be achieved with the software.
The tutorials will be given a series of outstanding experts Christian Lemmen (BioSolveIT), Akos Tarcsay (ChemAxon), Giovanna Tedesco (Cresset), Dan Ormsby (Dotmatics) Greg Landrum (Knime ) and Matt Segall (Optibrium), you will be able to install the software packages on you own laptops together with a license to allow you to use it for a limited period after the event.
Registration opened just before Christmas and apparently there were a number of people sign up over the festive period. Remember there are a limited number of places and it is first come first served.
Registration and full details are here.
Also a free one-day symposium Streamlining Drug Discovery" in Frankfurt
The very successful symposia series "Streamlining Drug Discovery" comes to Frankfurt on 14 February 2019. Jointly BioSolveIT, Optibrium, Lhasa and Elsevier invite you for this free one-day event highlighting new approaches and technologies being applied to the search for future therapeutics. For further details please visit the symposium website https://www.biosolveit.de/symposium/2019-02-14/
An interesting review DOI
Discovery and development of 210 new molecular entities (NMEs; new drugs) approved by the US Food and Drug Administration 2010–2016 was facilitated by 3D structural information generated by structural biologists worldwide and distributed on an open-access basis by the PDB. The molecular targets for 94% of these NMEs are known. The PDB archive contains 5,914 structures containing one of the known targets and/or a new drug, providing structural coverage for 88% of the recently approved NMEs across all therapeutic areas. More than half of the 5,914 structures were published and made available by the PDB at no charge, with no restrictions on usage >10 years before drug approval. Citation analyses revealed that these 5,914 PDB structures significantly affected the very large body of publicly funded research reported in publications on the NME targets that motivated biopharmaceutical company investment in discovery and development programs that produced the NMEs.
As 2019 starts I'd like to wish you all a Happy New Year and hope for great success in your drug discovery endeavours.
The Drug Discovery Resources website continues to increase in popularity with over 147,000 page views, an increase of 8% over the figure for 2017. The pages were visited by over 72,500 viewers and around a third of the visitors come back on multiple occasions suggesting they find it useful. The visitors come from 172 different countries with the US (32%), UK (13%) and India (8%) topping the list.
The most viewed pages in 2018 were
- Distribution and Plasma Protein Binding
- Calculating Physicochemical Properties
- Molecular Interactions
- Kinase Inhibitors
- Aspartic Acid Protease Inhibitors
- Solvation and desolvation
- Hit Identification
- CYP Interactions
- Acid Bioisosteres
- Fragment based screening
There have been a number of significant updates to the Drug Discovery Resources this year, in particular, a new section on Macrocycles which has proved very popular. The Target Validation section has been updated several times, as has the Molecular Interactions page and I'm grateful for readers who have pointed out relevant recent publications.
Looking at the operating systems 56% are Windows users, 20% Mac users, 10% iOS and 10% Android, Chrome dominates the browser stats (64%) with Safari second (17%) and Firefox third (10%).
The latest update to the Open Targets Platform has been released (18.12).
Centre for Therapeutic Target Validation is a pre competitive public-private venture that aims to provide evidence on the biological validity of therapeutic targets and provide an initial assessment of the likely effectiveness of pharmacological intervention on these targets, using genome-scale experiments and analysis. The platform currently contains 28,931 targets, 3,049,882 associations for 10,053 diseases.