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Cambridge MedChem Consulting

31st symposium on Medicinal Chemistry in Eastern England

The Symposium on Medicinal Chemistry in Eastern England, known colloquially as the "Hatfield MedChem" meeting, is a highly successful, long-standing, one-day meeting which runs annually. The scientific program comprises of presentations showcasing medicinal chemistry case studies from tools to candidates, across a range of modalities, therapeutic areas and target classes, as well as covering more general topics from the forefront of drug discovery of relevance to medicinal chemists. The meeting aims to be informal and interactive and the event will offer excellent scientific and networking opportunities for all those working in medicinal chemistry and drug discovery.

It will take place on Thursday 30th April 2020 at The Fielder Centre, Hatfield, Hertfordshire, UK

Registration is now open.

Full details of the scientific programme and registration details are on the website https://www.maggichurchouseevents.co.uk/bmcs/hatfield_symposium-31.htm

Always a very popular meeting so registration early is recommended.

Twitter hashtag #HatfieldMedChem20

Phenotypic Screening now offered by the European Lead Factory

The European Lead Factory has announced that it can now offer two types of phenotypic screening:

  • A high-throughput, but “lower content” phenotypic approach that is suited to screening ELF’s entire compound collection, and
  • A more complex “high content” screening approach using microscopy or flow cytometry to probe phenotype on a smaller subset of the compound collection

While low content assays can be live measurements or have fixed end points and involve well-averaged readouts, high content assays can be much more complex, based on live or fixed cells, multiple cell types and usually have more than one parameter as a readout. The complexity of the latter workflow makes it better suited to being performed on a smaller representative subset of the large collection.

Phenotypic screening historically has been the basis for the discovery of many drugs. Compounds are screened in cellular or animal disease models to identify compounds that cause a desirable change in phenotype. Only after the compounds have been discovered are efforts made to determine the biological targets of the compounds - a process known as target deconvolution.

Proposals for phenotypic screening approaches follow the normal review and selection process. A dedicated application form is available here.

The submission deadline for the next review and selection round is February 7, 2020.

EFMC Prize for a Young Medicinal Chemist in Industry/Academia

I just thought I'd highlight this award.

The EFMC created the “EFMC Prize for a Young Medicinal Chemist in Industry/Academia” as we felt it was important to acknowledge and recognise outstanding young medicinal chemists (≤ 12 years after PhD) working in European industry and academia. The 2020 Prizes will be given at the XXVI EFMC "International Symposium on Medicinal Chemistry" (EFMC-ISMC 2020) to be held in Basel, Switzerland on September 6-10, 2020. Both prizes consist of a diploma, an invitation to give an oral communication at the EFMC-ISMC, and a cash prize of € 1,000.

To find out more on the regulations and the application procedure visit the EFMC website: https://www.efmc.info/prizes, closing date Jan 31 2020.

Drugs approved by EMA in 2019

I recently posted details of the small molecule drugs approved by the FDA in 2019. This generated considerable interest and I thought it might worthwhile doing a similar thing for the drug approvals in Europe. However this turns out to be less straight-forward, medicines can be authorised in several European countries simultaneously by using one of three procedures: the 'centralised procedure', the 'mutual-recognition procedure' or the 'decentralised procedure'. Medicines can also be authorised in a single Member State by using the national authorisation procedure of that country. The European Medicines Agency is responsible for the centralised procedure so I downloaded just the drugs approved via this mechanism.

Of the 61 approvals in 2019, 45 were small molecule drugs and 16 were biologics. The structures of the small molecules are shown below

Structures

Looking at the calculated physiochemical properties of the small molecules one thing is quite interesting, around 50% are predicted to be ionised at physiological pH.

abzn2019

As shown in the plot below (Blue = small molecules, Green = Biologics) the largest group of drugs were Antineoplastic agents, the next largest groups being anti-virals and immunosuppressants.

TherapeuticTargets

Biosimilars

Four "biosimilars" were also approved. Kromeya and idacio both of which contain adalimumab (Humira) a TNF-alpha inhibitor as the active ingredient. Adalimumab was the first fully human monoclonal antibody approved by the FDA in 2002.

Grasustek contains the active substance pegfilgrastim (Neulasta) a PEGylated form of the recombinant human granulocyte colony-stimulating factor (GCSF) analog filgrastim. Zirabev contains the active substance bevacizumab (Avastin) that blocks angiogenesis by inhibiting vascular endothelial growth factor A (VEGF-A).

These four drugs join a number of other biosimilars approved in Europe, with the UK in particular keen to move to biosimilars. Biosimilars are expected to save the EU up to $44 billion in health care costs by 2020 LINK.

Most important, the EU is realizing the benefits of biosimilars without sacrificing safety or quality. Of the biosimilars approved since 2006, none have been withdrawn or suspended for safety or efficacy reasons. Further, regulators have not identified any differences in the nature, severity or frequency of adverse effects between biosimilars and biologics.

Fragment based screening pages updated

I spent some time over the Christmas break updating the Drug Discovery Resources pages on Fragment-Based screening, adding new vendors and updating the physicochemical profiles. I've also added some discussion on the elaboration/optimisation of fragments.

The pages are

Fragment-Based Screening
Building a Fragment Collection
Available Fragment Collections
Profiles of Fragment Collections
Fragment-Based Screening Published Hits

The published fragments contains details of fragments that have been reported as hits in the literature, this database now has over 1500 entries culled from over 310 publications directed at nearly 220 different molecular targets using 26 different detection technologies.

TargetTypes

It could be argued that published fragment hits perhaps gives us an insight into the best fragments to include in library design.

Small molecules approved by FDA in 2019

Drug approvals from the FDA in 2019 a total of 48 with the "small" molecules shown below.

FDAapprovals2019

Calculated physicochemical properties for the individual components (I guess some are not so small).

FDA2019

Seasons Greetings

Have a great time and a successful New Year, it's a beautiful world let's make sure it is still there for future generations.

IMG_7695

As usual any monies saved on cards will be donated to the MS Society

LogP/D page updated

The page on LogP and LogD is one of the most frequently read and it has been updated to include recent publications.

Lipophilicity is possibly the most important physicochemical property of a potential drug, it plays a role in solubility, absorption, membrane penetration, plasma protein binding, distribution, CNS penetration and partitioning into other tissues or organs such as the liver and has an impact on the routes of clearance. It is important in ligand recognition, not only to the target protein but also CYP450 interactions, HERG binding, and PXR mediated enzyme induction.

The contributions of various functional groups to LogD has been explored "LogD contributions of substituents commonly used in medicinal chemistry" DOI, this study used matched molecular pairs analysis of experimental LogD values from several thousand compounds collected using the shake-flask method at pH = 7.4. They reported the average deltaLogD difference for particular molecular pairs. I've compared these experimental results with calculated LogD.

MMPLogDfragsmall

ADME pages updated

I've spent a while updating the ADME section of the Drug Discovery Resources. I particular I've added a little on the Developability score DOI that identifies four distinct cLog P/molecular weight regions that define optimal and sub-optimal chemical space. I've also added a couple of useful references.

In addition, I've expanded the Absorption and Bioavailability page to include more on bioavailability with links to physicochemical properties. The Distribution and Plasma Protein Binding section has a couple of extra examples demonstrating the impact plasma protein binding has on other pharmacokinetic properties. I've added a few details of in vitro assays to the Transporters page, and expanded the in silico brain penetration models section.

The section on Aldehyde oxidase has been greatly expanded and now includes a section on prediction and mitigation, and added useful references.

ao_substrates

BioBlocks

I've added a new entry on to the available fragments page, BioBlocks is a newcomer to the field of fragment collections. Whilst many collections are culled from available compound collections using calculated property filters (eg Rule of 3), BioBlocks have designed novel fragments and as such there is negligible overlap with other collections. One concern with bespoke fragments is that it is often a challenge to find related analogues for followup. The BioBlocks Comprehensive Fragment Library (CFL) is a subset generated from a >1 million member synthesizable virtual library, so follow up compounds can be generated using proven in house chemistry.

BioBlocks