Summary of BMCS 2nd Conformational Design in Drug Discovery Conference 2025
The Discovery Centre – AstraZeneca, Cambridge, UK
Earlier this week, we had the pleasure of attending the 2nd Conformational Design conference held at The Discovery Centre, AZ; this also afforded us the opportunity to have a look at The Disc building, which is very nice. We had the exhibition stand and attended the talks: here are some highlights and references with a bit of MedChemica insight added.
The conference kicked off with Ruth Dooley from Evotec (“Harnessing Conformational Drivers in Drug Discovery”). Ruth described the analysis of matched pairs of compounds where often a simple change in substituent produced a profound effect. A lot of these could be rationalised by a significant change in the shape of the molecule. Three effects were described: Allylic group, CH-∏ interactions and Gauche effects – these were captured in the publication by Ruth:
[Progress in Med.Chem. 2024, 63, 1-60
Of these, I have personally observed the effect of the methyl group taking an axial position in a ring when proximal to an amide (see Cat K inhibitor). J. Med. Chem. 2012, 55, 8827−8837)
Please also see : – “Non-Additivity Analysis” – Christian Kramer, JCIM
Bernd Kuhn from Roche gave an excellent talk “Leveraging Conformational Insights for Efficient Inhibitor Design Against Neurological Targets”. The key finding was the addition of an amide group that resulted in an internal-H-bond as well as making interactions with the protein.
Interestingly, the same did not occur with a simple amide; both methyl groups were required to help orientate the group for the H-bond. This also only worked with 5 membered rings i.e. 6 membered rings had lower binding efficiency as the H-bond was not made. Bernd also discussed a series of MAGL inhibitors.
Thomas Fuchss from Merck presented on the discovery of the ATM kinase inhibitor, lartesertib. This program found a dramatic “magic methyl” effect. The methyl on the pyrazole ring is close enough to the benzene to force rotation and lock out the ring. With the change in shape yielded improving the solubility and overall profile. The inability of the ring to rotate yielded atropisomers. The process chemists found a way to resolve the isomers late stage and give a >50% yield of the desired isomer. Apologies we were unable to find a publication of this work.
Henrik Möbitz from Novartis had analysed projects with Beyond Rule Of Five (bRo5) compounds and proposed a useful way of examining compounds by plotting Neutral TPSA against molecular weight – in this plot there is a channel where compounds are in the ideal space. Looking at these, it showed the compounds with bio-availability bRo5 could have higher molecular weight [Design Principles for Balancing Lipophilicity and Permeability in beyond Rule of 5 Space]. ChemMedChem, 2024, 19(5)
Henriette Willems (University of Cambridge) described her group’s work on PI5P4K Inhibitors, which has been published. The second half of her talk described experiments with protein folding algorithms and compared Boltz-1, Alpha Fold 3, RoseTTAFold to see if they could predict any of the results. Each method required some degree of pocket conditions to improve performance. RSC Med. Chem., 2023, 14, 2035-2047
In a similar manner Joseph Bluck (Bayer AG) examined recent projects to see if folding AI models could find the hit compounds from projects and thus showed the value of these to future projects. 20 targets were selected that did not have a single structure in the PDB, thus the folding algorithms could not have been trained on them. The results were a mixed bag with no clear winner.
Ed Harder from Schrodinger, gave a history of the OPLS molecular mechanics force field evolution leading to the latest development of OPLS5.
Fabio Montisci from Cambridge Crystallographic Data Centre gave a very interesting talk on the optimisation of PROTACs using knowledge from the CCDC.
There were two talks on cyclic peptides: Jovan Damjanovic (Novo Nordisk) – Synergistic AI/physics approach to structure-based design of druglike peptidic macrocycles and Gustavo Bezerra (Bicycle Therapeutics) – Identification of potent ACE2 binders via unique phage display: conformational insights and therapeutic potential.
The last talk of the day was from Elena de Orbe Izquierdo (AstraZeneca). Anti-body drug conjugates have advanced in recent years and a critical part of the design is the optimisation of the linker between the antibody and the war-head. Elena described a process of using MD simulations to rank ideas for these linkers.
Lampros Millanos from Charles River won the best poster competition – well done to him.
A thank you to the conference organisers for pulling together an excellent program.
Markus Schade, AstraZeneca (Chair); Chris Swain, Cambridge MedChem Consulting (Treasurer); Luca Carlino, AstraZeneca; Tim Barrett, GSK; Martin Swarbrick, Ryvu Therapuetics; A. Ganesan, University of East Anglia
