In an excellent publication "Where do recent small molecule clinical development candidates come from?" DOI, the authors give a detailed description on the development of clinical candidates from the initial hit. They also define the changes in physicochemical properties.
An analysis of physicochemical properties on the hit-to-clinical pairs shows an average increase in molecular weight (ΔMW = +85) but no change in lipophilicity (ΔclogP = −0.2), although exceptions are noted. The majority (>50%) of clinical candidates were found to be structurally very different from their starting point and were more complex.
I thought it might be interesting to look at the calculated properties of the 66 clinical candidates. Interestingly many have molecular weights > 500 and only around 30% contain an ionisable group. All structures contain an aromatic ring and 48 molecules contain 3 or more aromatic rings.
In case anyone was wondering the high molecular weight compounds are not peptides or macrocycles.
The Molecular Interactions page has been updated to include a section on anion-aryl interactions.
Just announced. Open Targets Platform release - 18.08.
In this release there is now data on:
- 21,149 targets
- 10,101 diseases
- 6.5 million pieces of evidence
- 2.9 million associations between targets and diseases
The Open Targets Platform is a comprehensive and robust data integration for access to and visualisation of potential drug targets associated with disease. It brings together multiple data types and aims to assist users to identify and prioritise targets for further investigation. A drug target can be a protein, protein complex or RNA molecule and it’s displayed by its gene name from the Human Gene Nomenclature Committee, HGNC. We integrate all the evidence to the target using Ensembl stable IDs and describe relationships between diseases by mapping them to Experimental Factor Ontology (EFO) terms. The Platform supports workflows starting from a target or disease, and shows the available evidence for target – disease associations. Target and Disease profile pages showing specific information for both target (e.g baseline expression) and disease (e.g. Disease Classification) are also available
A couple of people have asked me how to access the category tags that are attached to news items, the short answer is not easily so I've created a new tab at the top of the page that gives you direct access.
Click on the link and you will get an alphabetical listing of all categories with appropriate links.
It may take a day or so for the new menu bar to appear on all pages.
Clinical trials can be extremely lengthly and there have been many discussions about how to get medicines to patients more efficiently than the seemingly bureaucratic process that is currently in place.
Real-Time Oncology Review Pilot Program is a project to try and reduce the time needed to gain approval.
There are important caveats though.
Submissions to be considered for the RTOR pilot should meet the following criteria:
Drugs likely to demonstrate substantial improvements over available therapy, which may include drugs previously granted Breakthrough Therapy Designation for the same or other indications. Drugs meeting other criteria for other expedited programs (e.g. fast track, priority review) may also be considered. Straight forward study designs, as determined by the review division and the OCE. Studies conducted exclusively outside the United States and adjuvant, neoadjuvant, and prevention studies will be excluded. Endpoints that can be easily interpreted (for example, overall survival in a randomized trial). Supplements with CMC formulation changes and supplements with pharmacology/toxicology data will be excluded. Submissions with greater complexity, including those with companion diagnostics, may also be excluded for the purposes of the pilot program.
The real time review means the FDA can continuously review data as it is produced and give early feedback.
RTOR allows the FDA to review much of the data earlier, before the applicant formally submits the complete application. First, the applicant will present topline data for the FDA to determine whether RTOR would be appropriate for the supplement. If the agency determines RTOR is an appropriate review pathway, the applicant can start sending pre-submission data to the agency, under the original NDA/BLA, 2-4 weeks after all patient data has been entered and locked by the applicant in their database
This sort of process may be ideal for some indications where the trials give clear end points, survival in oncology, clearance of parasite in Malaria or other infectious diseases. Clinical trials for Psychiatric disease, marginal improvements over existing therapy or slowly progressing neurological diseases will probably not be suitable.
Boehringer Ingelheim has added it's well-characterised non-covalent ATP-competitive inhibitor of glycogen synthase kinase (GSK-3) Bi-5521 to its open molecule platform opnMe.com.
opnMe.com, the new open innovation portal of Boehringer Ingelheim, aims to accelerate research initiatives and enable new disease biology in areas of high unmet medical need by sharing well-characterized, best-in-class, pre-clinical tool compounds.
BI-5521 is a potent and selective ATP-competitive small molecule inhibitor of glycogen synthase kinase 3 (GSK-3), GSK-3β (IC50) 1.1 nM, with demonstrated in vivo activity. Rat pharmacokinetics are available, together with an inactive related compound.
Another useful tool for Target Validation.
The full agenda for the Macrocycles 2018 meeting 8th-9th October 2018 is now available and it looks to be a great meeting.
Full details of the meeting and registration is available online here http://www.maggichurchouseevents.co.uk/bmcs/macrocycles_2018-online%20registration.htm.
Off-target activity is often ignored and might only be uncovered relatively late in the drug discovery program. Whilst broad spectrum screening is available it can be rather expensive. Predicting potential off-target activities is an attractive approach and this paper describes the development of a prediction tool using nearest neighbours combined with machine learning.
The Polypharmacology Browser PPB2: Target Prediction Combining Nearest Neighbors with Machine Learning DOI
To build PPB2 we collected a bioactivity dataset of all compounds having at least IC50 < 10 uM on a single protein target in ChEMBL22 considering only high confidence data points as annotated in ChEMBL and only targets for which at least 10 compounds were documented
You can try it out here PPB2., depending on the model chosen the results are calculated in a couple of minutes, but don't post your proprietary molecules. Typical results are shown below, clicking on the green "Show NN" button shows the most similar structures.
The first circular for the 20th SCI/RSC Medicinal Chemistry Symposium (aka the Cambridge MedChem Meeting) has been announced. This is also a call for abstracts for both oral and poster submissions. Potential contributions should be communicated to the secretariat at firstname.lastname@example.org by Friday 9th November 2018.
You can download the full details of the meeting here PDF.
A number of outstanding talks have already been confirmed.
Opportunity to apply for a share of up to £20 million to deliver game changing or disruptive innovations with significant potential for impact on the UK economy in partnership with Medicines Discovery Catapult.
Secure the funding you need to progress your projects towards commercialisation. Use our dedicated grant application team to ensure your submissions stand the best chance of success. Our experienced commercial and scientific teams have connections across industry, academia, finance, government, and research networks – we can help take your projects further towards commercial viability.
I've also compiled a page on Grant funded Research