I’ve updated the Drug Discovery Resources to include a page on Kinase Inhibitors. I will be expanding it over the next week, so any comments or suggestions welcome.
ChEMBL_18 has just been released.
- 1,566,466 compound records
- 1,359,508 compounds (of which 1,352,681 have mol files)
- 12,419,715 activities
- 1,042,374 assays
- 9,414 targets
- 53,298 documents
They now include epigenetic targets, and several new web services giving drug approvals and mechanisms.
Target validation is the most critical step in drug discovery because as the chemists will tell you “Most of the other things we can fix”, so I was delighted to hear about the new Centre for Therapeutic Target Validation.
You can read more about it in the Press release
”The Centre for Therapeutic Target Validation is a transformative collaboration to improve the process of discovering new medicines,” says Dr Birney. “The pre-competitive nature of the centre is critical: the collaboration of EMBL-EBI and the Sanger Institute with GSK allows us to make the most of commercial R&D practice, but the data and information will be available to everyone. It is truly exciting to apply so many different areas of expertise, from data integration to genomics, to the challenge of creating better medicines.”
I wish them every success and will be following their work closely.
It is interesting to see how commercial fragment libraries are starting to evolve, from simple molecular weight cuts of available chemicals to more careful selection based on physicochemical properties. We now see several interesting design strategies being adopted.
Those based on a screening technology such as the LifeChemicals Fluorine-based library to support 19F NMR-based fragment screening, and the Maybridge Bromo-Fragment Collection a collection of over 1500 bromine containing Maybridge fragments constructed as an aid to X-ray based fragment screening.
Other libraries are designed for specific targets
OTAVA offers you new Chelator Fragment Library that comprises 575 compounds in total, Chelators demonstrate binding affinities suitable for FBLD screening and provide a diverse range of molecular platforms from which to develop lead compounds. Also, the propensity for chelators to bind metal ions allows for better prediction of their probable binding position within a protein active site in the absence of experimental structural data of the complex.
Many attractive drug targets contain a free sulfhydryl group in the active site that confounds functional HTS assays due to its facile, non-specific oxidation leading to target inhibition. AnCore have developed a Targeted Covalent Inhibitor fragment library (TCI-Frag™) containing 100+ Rule-of-3 compliant fragments are conjugated with mildly reactive functionalities. The BIONET CNS Fragment Library is a focused library containing 700 Fragments selected for their suitability for Fragment Based Lead Discovery in the areas of CNS drug discovery and Universal target classes.
I’ve updated the Fragment Collections page
I’ve just been sent details of a new medicinal chemistry course.
This course explores how to bring a drug from concept to market, and how a drug's chemical structure relates to its biological function. The course opens with an introduction to the drug approval process. This introduction combines the social, economic, and ethical aspects of drug discovery. Topics include how diseases are selected for treatment, the role of animal testing, and the costs of various discovery phases. The course then focuses on the scientific side of drug discovery. Topics include how drugs interact with biological molecules, drug absorption and elimination, and the discovery of weakly active molecules and their optimization into viable drugs.
The course starts 10 March, it is estimated the course will require 6-8 hours per week and runs for 7 weeks. The course was organised by Erland Stevens who wrote the medchem textbook Medicinal Chemistry: The Modern Drug Discovery Process.
Beating cancer through a space game never seemed possible. Until now….
Every day, scientists across the globe are painstakingly analysing the genetic faults in thousands of cancer samples. They are looking for clues that will help develop new cancer treatments. This game let’s you help.
Play to Cure™: Genes in Space is a pioneering way of helping these scientists in their mission to beat cancer sooner and all via this world first mobile game supported by Cancer Research UK.
A mysterious substance is discovered in the voids of deep space. Dubbed Element Alpha, the substance is refined for use in medicine, engineering and construction and soon the Element Alpha industry explodes galaxy wide…..
I’ve updated the page on Aldehyde Oxidase, an enzyme in metabolism of a wide variety of nitrogen heterocycles.
I’ve also included A recent publication DOI that suggests a simple test for the early identification of heteroaromatic drug candidates that have a high probability of metabolism by AO. Bis(((difluoromethyl)sulfinyl)oxy)zinc (DFMS) was used as a source of the CF2H racial, simple LCMS was then used to identify a characteristic M+50 peak. It is also possible to scale up and isolate these metabolically blocked compounds and retest them for improved qualities.
I’ve just updated the page on HERG activity, I’ve included the results of matched pair analysis conducted on the database of berg activity that I have been compiling.
Whilst much computational work is undertaken to support, library design, virtual screening, hit selection and affinity optimisation the reality is that the most challenging issues to resolve in drug discovery often revolve around absorption, distribution, metabolism and excretion (ADME). Whilst we can measure the levels of parent drug in various medium tracking metabolic fate can often be a considerably more difficult proposition requiring significant resources. For this reason prediction of sites of metabolism has become the subject of current interest.
FAME DOI is a collection of random forest models trained on a comprehensive and highly diverse data set of 20,000 small molecules annotated with their experimentally determined sites of metabolism taken from multiple species (rat, dog and human). In addition dedicated models are available to predict sites of metabolism of phase I and II processes.
FAME offers a high performance prediction of sites of metabolism mediated by a wide variety of mechanisms.