I've updated the Molecular Interactions page on the Drug Discovery Resources site.

https://www.cambridgemedchemconsulting.com/resources/molecular_interactions.html

Just catching up with my reading, I've always been a fan of compounds with slow off-rates and the impact on duration of action.

The situation was elegantly summarised in a publication from earlier in the year from Copeland et al. DOI

A dominant assumption in pharmacology throughout the 20th century has been that in vivo target occupancy-and attendant pharmacodynamics-depends on the systemic concentration of drug relative to the equilibrium dissociation constant for the drug-target complex. In turn, the duration of pharmacodynamics is temporally linked to the systemic pharmacokinetics of the drug. Yet, there are many examples of drugs for which pharmacodynamic effect endures long after the systemic concentration of a drug has waned to (equilibrium) insignificant levels. To reconcile such data, the drug-target residence time model was formulated, positing that it is the lifetime (or residence time) of the binary drug-target complex, and not its equilibrium affinity per se, that determines the extent and duration of drug pharmacodynamics.

I've added it to the page on separation of PK and PD in the Drug Discovery Resources

A recent publication describes the continued evolution of the AlphaFold Protein Structure Database created by EMBL-EBI and DeepMind. From an initial 300K structures it now contains 214 million predicted protein structures.

You can read the paper here DOI.

The AlphaFold Database Protein Structure Database (AlphaFold DB, https://alphafold.ebi.ac.uk) has significantly impacted structural biology by amassing over 214 million predicted protein structures, expanding from the initial 300k structures released in 2021. Enabled by the groundbreaking AlphaFold2 artificial intelligence (AI) system, the predictions archived in AlphaFold DB have been integrated into primary data resources such as PDB, UniProt, Ensembl, InterPro and MobiDB. Our manuscript details subsequent enhancements in data archiving, covering successive releases encompassing model organisms, global health proteomes, Swiss-Prot integration, and a host of curated protein datasets. We detail the data access mechanisms of AlphaFold DB, from direct file access via FTP to advanced queries using Google Cloud Public Datasets and the programmatic access endpoints of the database. We also discuss the improvements and services added since its initial release, including enhancements to the Predicted Aligned Error viewer, customisation options for the 3D viewer, and improvements in the search engine of AlphaFold DB.

Just got details of this announcement of the latest person to be inducted into the Royal Society of Chemistry BMCS Hall of Fame.

The BMCS is delighted to announce that Professor Andrew Hopkins, FRS FMedSci FRSC, will be the 2023 inductee to its Hall of Fame, and the recipient of the associated medal.

Andrew is widely recognized for his seminal contributions to the use of informatics in drug design. His contributions have been highly impactful as evidenced by his highly cited papers in the area of Ligand Efficiency (LE), Chemical Beauty (QED) as well as the “druggable genome”. Andrew has been an early pioneer for the use of artificial intelligence (AI) and machine learning (ML) in drug discovery, and whilst it is a nascent field, it holds much potential for impact in the future. Combining his drug discovery expertise with his entrepreneurial spirit, Andrew founded and is leading, as Chief Executive, Exscientia plc, an AI-driven company dedicated to changing the way drugs are discovered. He led the teams that discovered the first drugs to enter human clinical trials, which were designed with the extensive use of ML and AI generative methods.

Andrew joins a fantastic group of individuals who have all made outstanding contributions to drug discovery.

Dr Karin Briner, Professor Dame Carol Robinson, Dr David Rees, Sir Simon Campbell, Professor C Robin Ganellin,

In drug discovery the introduction of fluorine into potential drug candidates is an essential part of the medicinal chemists toolbox. Blocking a metabolic hotspot by replacing a Hydrogen by Fluorine or deactivating and aromatic ring by adding a trifluoromethyl are well established strategies for reducing metabolism, increasing half-life and reducing drug load. There are more details on the metabolism page and influence [pi-stacking interactionshttps://www.cambridgemedchemconsulting.com/resources/molecular_interactions.html).

I have a database of all drugs that have been reported to be in phase 3 trials or later (not all will have made it to market) and it is interesting to see how many contain a fluorine atom of some kind. As expected Aryl F and CF3 are the most common

A few examples are shown below.

There are also other classes of molecules like perflexane which is used as an imaging contrast agent in echocardiogram. Halothane used clinically as an inhalational anesthetic (on the WHO Model List of Essential Medicines) and other inhaled anesthetics.

So at first sight the EFMC statement was of some concern.

EFMC STATEMENT ON EU PROPOSAL TO BAN PFAS The EU, through the European Chemicals Agency (ECHA), has launched a proposal that aims to extensively restrict the manufacture, supply, and use of all per- and polyfluoroalkyl substances (Ref 1). PFAS are a large class of synthetic chemicals that are used across a broad range of activities in different scientific areas, not restricted to chemistry. However, several PFAS are environmental pollutants and some of them have detrimental effects on human health. Their extensive use throughout the society, combined with the low reactivity displayed by many fluoroalkyl chemicals, magnifies the potential for accumulation in the environment and contamination of food and water supplies. According to this proposal, which is in public consultation until September 25th (ref 2), PFAS encompasses "any substance that contains at least one fully fluorinated methyl (CF3) or methylene (CF2) without any H, Cl, Br, or I attached to it"

However, looking at the generic scope in more detail it appears that the scope might not be as all encompassing. Looking at the description here https://echa.europa.eu/registry-of-restriction-intentions/-/dislist/details/0b0236e18663449b. The generic scope is described as shown below and I've highlighted a critical phrase.

Per- and polyfluoroalkyl substances (PFASs) defined as: Any substance that contains at least one fully fluorinated methyl (CF3-) or methylene (-CF2-) carbon atom (without any H/Cl/Br/I attached to it).

A substance that only contains the following structural elements is excluded from the scope of the proposed restriction:

CF3-X or X-CF2-X’,

where X = -OR or -NRR’ and X’ = methyl (-CH3), methylene (-CH2-), an aromatic group, a carbonyl group (-C(O)-), -OR’’, -SR’’ or –NR’’R’’’,

and where R/R’/R’’/R’’’ is a hydrogen (-H), methyl (-CH3), methylene (-CH2-), an aromatic group or a carbonyl group (-C(O)-).

My interpretation (caveat I'm not a lawyer) is that the vast majority of drugs, reagents and solvents like trifluoro acetic acid would be excluded. However, inhaled anesthetics and the contrast imaging agents would be included. So the pharma industry needs to be included in the dialog but drugs themselves might have limited impact.

I've not covered polymers, and PTFE is is used in much laboratory equipment from stirrer bars, stopcocks, O-rings, seals etc. and who hasn't used PTFE tape on ground glass joints. There may be alternatives that I'm not aware of, but any substance that has similar properties of inertness, durability etc. may cause the same concerns as PFAs.

The European Chemicals Agency invites interested parties to send in scientific and technical information on the manufacture, placing on the market and use of per- and polyfluoroalkyl substances (PFAS) by 25 September 2023 https://echa.europa.eu/-/echa-seeks-input-on-proposed-pfas-restriction.

Diamond Light Source science facility in Oxfordshire will be upgraded through a £500 million investment.

https://www.gov.uk/government/news/uk-science-facility-that-kickstarted-covid-drug-development-granted-500-million-upgrade-fund.

Established in 2001 and opened in 2007, Diamond is a joint-venture between UKRI-STFC (86%) and the Wellcome Trust (14%).

The Diamond-II upgrade will take several years of planning and implementation. This will include a ‘dark period’ of 18 months with no synchrotron light for the user community, followed by a period to fully launch the new facility with three new flagship beamlines and major upgrades to many other beamlines.

UKRI have announced £13 invested in medical research projects. The projects aim to transform health using artificial intelligence (AI) to assist and refine diagnostics and procedures

https://www.ukri.org/news/13-million-for-22-ai-for-health-research-projects/

Includes image analysis in oncology, keyhole surgery, NLP analysis of clinical data and treatments for chronic pain.

The next UKQSAR meeting will be held at the University of Liverpool on September 14th 2023.

The meeting will take place at building 502, University of Liverpool (see D6 in campus map).

More information will be available on the website https://ukqsar.org/index.php/2023/07/19/uk-qsar-autumn-2023-meeting/

The schedule will be:

9.00-10.00 Registration (coffee/tea/refreshments) 10.00-10.15 Welcome – Nathan Brown (UK QSAR Chair)

10.15-11.45 Session 1 – Chair Neil Berry (University of Liverpool) 10.15-10.45 Talk 1– Alessandro Troisi (University of Liverpool) 10.45-11.15 Talk 2 – Abbie Trewin (University of Lancaster) 11.15-11.45 Talk 3 – Lauren Reid (Medchemica Ltd.) 11.45-12.45 Lunch and poster session

12.45-13.45 Session 2 – Chair Andrew Leach (University of Manchester) 12.45-13.15 Talk 4 – Steve Enoch (Liverpool John Moores University) 13.15-13.45 Talk 5 – Rachel Pirie (University of Newcastle) 13.45-14.15 Break (coffee/tea/refreshments) and poster session

14.15-15.45 Session 3 – Chair Steve Maginn (CCG) 14.15-15.15 Talk 6 – Elena De Orbe (AstraZeneca Ltd.) 15.15-15.45 Talk 7 – Adam Nelson (University of Leeds) 15.45-16.00 Conclusion and poster prizes - Nathan Brown (UK QSAR Chair)

Please register using the online form.

We are delighted that the RSC CICAG group (Chemical Information and Computer Applications Group) have been able to offer two travel bursaries for students to attend the meeting in return for providing a short write-up for the group. If you would like to apply for the bursary please use the form

Just saw this.

The AlphaFold Protein Structure Database, a result of a collaborative effort between Google DeepMind and EMBL’s European Bioinformatics Institute (EMBL-EBI), has released an exciting update to its web pages, providing users with an enhanced experience. This update marks a significant step in facilitating the use of AlphaFold structure data.

One of the most interesting updates are the improvements to the 3D viewer Mol*.

Full details are here https://www.ebi.ac.uk/about/news/updates-from-data-resources/alphafold-database-ux-update/.

Just got this message, the UKQSAR meetings are always excellent

We are pleased to announce that the next UKQSAR meeting will be held at the University of Liverpool on September 14th 2023.

The schedule will be: 09.00-10.00 Registration 10.00-16.00 Scientific programme

Please register using the online form: https://forms.office.com/e/RR5qGKGCwJ

We are delighted that the RSC CICAG group (Chemical Information and Computer Applications Group (rsccicag.org) have been able to offer two travel bursaries for students to attend the meeting in return for providing a short write-up for the group. If you would like to apply for the bursary please use the form: https://forms.office.com/e/yiNi4VFuZD

As usual, there is no cost to register for the meeting and we are grateful for MedChemica Ltd. for supporting the catering costs.

There will be plenty of opportunity for posters to be presented and discussed over lunch and coffee, please indicate if you would like to present a poster in the registration.

Information about travel options are available from the University of Liverpool website: https://www.liverpool.ac.uk/study/international/coming-to-liverpool/getting-here/ https://www.liverpool.ac.uk/maps/visiting/car-parking/ We would urge you to consider the environment when planning your journey.