Artificial Intelligence and Augmented Intelligence for Automated Investigations for Scientific Discovery (AI3SD) are running an Online Guest Lecture Series this summer. The full seminar list is here.
If you missed a presentation or want to replay it, all the presentations are on the AI3SD YouTube channel.
The RSC Biological and Medicinal Chemistry initiated a Hall of Fame a short while ago and I'd like to highlight the relevant page of the BMCS website.
The Hall of Fame is to recognise prominent chemists for outstanding, sustained, contributions to any area of interest to the BMCS, eg medicinal chemistry, agriscience, biooorganic chemistry, chemical biology. This is an Individual award to recognise prominence and significant, sustained, scientific impact in the field of medicinal chemistry, agriscience or chemical biology, including teaching excellence, outstanding contributions to the BMCS, or any combination thereof.
The first inductee to the BMCS Hall of Fame was Professor C Robin Ganellin FRS, Emeritus Professor of Medicinal Chemistry at University College London. He co-discovered histamine H2-receptors with James Black and co-invented the anti-ulcer drug cimetidine. He co-discovered butabindide, an inhibitor of the enzyme tripeptidyl peptidase II, and co-invented the histamine H3-receptor antagonist drug, pitolisant.
Cimetidine was the first histamine H2 receptor antagonist drug that inhibits stomach acid production and used in the treatment of heartburn and peptic ulcers.
Oral bioavailability is 65% and it has a half-life of 2 hours.
Butabindide is an inhibitor of the enzyme tripeptidyl peptidase II designed as an anti-obesity drug.
The histamine H3-receptor antagonist Pitolisant, is used for the treatment of excessive daytime sleepiness (EDS) in adults with narcolepsy
Pitolisant is well absorbed (90%) and has an elimination half-life of 10-12 hours.
The 2019 inductee was Sir Simon Campbell CBE FRS FMedSci who is probably best known for his work leading to Doxazosin, for high blood pressure and angina and Amlodipine – used to treat high blood pressure and prostrate enlargement.
Doxazosin is a α1-selective adrenergic blocker in the quinazoline class of compounds
Oral bioavailability is 65% and elimination half-life 22 hours, , it highly plasma protein bound (98%). Hepatic metabolism of doxazosin produces inactive O-demethylated and C-hydroxylated metabolites.
Amlodipine is a long acting calcium channel antagonist, it blocks L-type calcium channels in muscle cells and N-type calcium channels in the central nervous system.
Amlodipine is well absorbed by the oral route with a mean oral bioavailability around 60%; the half-life of amlodipine is about 30 h to 50 h, it highly plasma protein bound (97.5%). Renal elimination is the major route of excretion with about 60% of an administered dose recovered in urine, largely as inactive pyridine metabolites. Amlodipine is on the World Health Organisation's List of Essential Medicines.
The COVID Moonshot is an ambitious crowdsourced initiative to accelerate the development of a COVID antiviral. We work in the open with no intellectual property constraints. This way, any scientist can view submitted drug designs and experimental data to inspire new design ideas. We use our cutting-edge machine learning tools and Folding@home's crowdsourced supercomputer to determine which drug designs to send to our partners to make and test in the lab. With each drug design tested, we get closer to our goal.
It is sometimes difficult to cross-reference compounds between multiple sources so I've downloaded the compounds with associated data calculated InChiKeys and then used the InChiKey to link compounds from different sources within Vortex. This means you have the biochemical data together with PDB code (if available) or the fragalysis code for the crystal structure. I've also annotated with identifiers from multiple databases (ChEMBL, PubChem etc.), calculated physicochemical properties (LogP/D, TPSA, HBD/A etc) and then exported in sdf format. I've also clustered the structures to aid navigation.
You can download the zipped sdf file here.
Updated. I was asked if I could provide this file in SMILES format so here it is.
I plan to try and have a look at ways to visualise the data when I can find some free time.
When helping to enhance screening collections I'm sometimes asked to exclude "prohibited precursor chemicals", these are chemicals that might be used in the manufacture of illegal drugs.
The effective control of chemicals used in the illicit manufacture of narcotic drugs and psychotropic substances is an important tool in combating drug trafficking. These chemicals, known as ‘precursors’, also have legitimate commercial uses as they are legally used in a wide variety of industrial processes and consumer products, such as medicines, flavourings and fragrances.
I'm aware of this list on the UK Government website https://assets.publishing.service.gov.uk/...PRECURSORCHARTDomesticJan2014.pdf, and the listing from INCB http://www.incb.org/documents/PRECURSORS/REDLIST/2020/RedList2020E.pdf, however I'm sure it far from complete.
Does anyone know of a more complete listing? Preferably in a chemically intelligent form
The SARS-CoV-2 main protease as drug target DOI
The unprecedented pandemic of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is threatening global health. The virus emerged in late 2019 and can cause a severe disease associated with significant mortality. Several vaccine development and drug discovery campaigns are underway. The SARS-CoV-2 main protease is considered a promising drug target, as it is dissimilar to human proteases. Sequence and structure of the main protease are closely related to those from other betacoronaviruses, facilitating drug discovery attempts based on previous lead compounds. Covalently binding peptidomimetics and small molecules are investigated. Various compounds show antiviral activity in infected human cells.
Remember a hit in a screen is just the very first step, there is much more to consider before it can be described as a drug candidate.
Interested in accessing a high quality high-throughput screening platform? Here is a chance to find out more about the European Lead Factory.
More details are here
The European Lead Factory (ELF) is a collaborative public-private partnership aiming to deliver novel lead molecules for drug discovery programs.
I've previously written about the ELF here.
As ever a useful analysis of the published literature on Practical Fragments, "Evaluation of 3-Dimensionality in Approved and Experimental Drug Space" DOI.
The true need for topological diversity in feedstocks and final drug molecules remains unclear given the overwhelming number of linear and planar drugs. The question remains as to whether more 3D compounds represent attractive and untapped therapeutic space, or if more linear/planar molecules are indeed the best topologies for bioactive molecules.
I came to a similar conclusion when looking at published fragment hits.
I wrote a blog entry about things that should be considered when proposing a hit identified from virtual screening as a drug candidate. Several people have suggested I create an easily identifiable web page so they can reference it. So here it is
I also thought I'd use the opportunity to look at the Drug Discovery Resources website stats for the first 6 months of 2020.
The Drug Discovery Resources pages are intended to act as a resource for scientists undertaking drug discovery, they were initially based on a course I give but have been expanded to give much more detail and to cover subjects not covered in the course.
The site has been viewed by almost 40,000 viewers with most people viewing a couple of pages per session. The viewers come from over 150 countries, the top countries being.
- United States (28%)
- United Kingdom (16%)
- India (9%)
- Germany (3.5%)
- China (3%)
- Canada (3%)
- Japan (3%)
The most viewed pages were
- Calculating Physicochemical Properties
- Distribution and Plasma Protein Binding
- Molecular Interactions
- Kinase Inhibitors
- Acid Bioisosteres
- Aromatic Bioisosteres
- Aspartic Acid Proteases
- Solvation and desolvation
- Fragment based screening
Looking at the operating systems 55% are Windows users, 20% Mac users, 12% iOS and 12% Android, Chrome dominates the browser stats (64%) with Safari second (17%) and Firefox third (7%).
A full-length model of glycosylated SARS-Cov-2 spike protein is recently described in literature by Casalino et. al. The PDB files for models are available at https://amarolab.ucsd.edu/covid19.php. These PDB files contain data for spike protein, glycans, lipid membrane, ions, and solvent.
Manish Sud has generated an annotated PyMol session file to view the model of spike protein present in open state conformation. The PyMOL session file is quite helpful during the reading of the article describing the work. It's a bit of elbow grease work to set up appropriate views in PyMOL and Manish has kindly shared it. It's available for download at http://www.mayachemtools.org/Download.html. I'm sure many will find it helpful.
The size of uncompressed PyMOL session file is quite large. It might take few minutes to load it into PyMOL, based on your hardware specifications.
Manish has also provided session files for SARS-CoV-2 Mpro ligands.
One of the best drug targets among coronaviruses is the main protease (Mpro), this enzyme is essential for processing the polyproteins that are translated from the viral RNA and the recognition sequence at most sites is Leu-Gln↓(Ser,Ala,Gly) and since no human enzymes have similar specificity inhibitors should be very specific. Mpro is a papain-like protease cysteine protease.
I've previously described the fragment hits from a fragment screen against crystals of the main protease (MPro) of SARS-CoV-2, the virus that causes COVID-19. Full details of the screening effort are described here https://www.diamond.ac.uk/covid-19/for-scientists/Main-protease-structure-and-XChem/Downloads.html
Additional biological results from project moonshot are now available. You can browse the data here https://postera.ai/covid/activity_data.
These results contain a significant milestone with the identification of the first sub micromolar non-covalent inhibitor.
JAG-UCB-a3ef7265-20 has been titrated twice now and has an IC50 of 0.6 uM.
This compound is a racemic mixture and the synthesis of the individual enantiomers is underway, if the activity predominantly lies with a single enantiomer we could see a further improvement in activity. The original submission was based on a pharmacophore search of Enamine based on amino-pyridine hits. I highlight this to underline the importance of simple descriptor-based searches, they are often highly competitive with sophisticated docking studies and require orders of magnitude less compute resources.
Since this research is being conducted in the public domain a number of other people have been able to contribute further ideas based on this exciting discovery.