Virtual Screening Strategies for Identifying Novel Chemotypes
In their recent article in Journal of Medicinal Chemistry, Stuart Lang and Martin Slater review in silico approaches for identifying ...
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The September meeting of EFMC-IMCS was in the picturesque city of Ljubljana, nestled amongst the surrounding mountains, with its many bridges, hilltop castle and numerous riverside eateries. The good food, wines and beers alone would have made the visit worthwhile, but there was more than enough excellent science to keep us in the conference centre.
With three separate scientific tracks: Therapeutic Areas, Technologies and Chemical Biology, it was impossible for the 800 plus delegates to see everything (much like an ACS meeting), but the busy schedule meant that there was something for everybody.
Fittingly, the opening on Sunday included a fascinating talk by the Slovenian academic and Zika virus expert Prof. Tatjana Avsic-Zupanc (University of Ljubljana) who was the first to characterize the link between Zika infection and foetal abnormalities and to identify a causative molecular target: PrM protein mutant S139N.
Bayard Huck (Merck Biopharm) presented his interpretation of their strategy towards the evolution of the medicinal chemist, a technology and multi-discipline embracing ‘Versatilist’, the scientist equivalent of a ‘Swiss army knife’. Bayard went on to describe virtual screening (one of Cresset Discovery Services’ areas of expertize) as vital for increasing cost-effectiveness. He also described the current mania with all things AI as being at the peak of inflated expectations in the Gartner hype cycle, although he noted that useful applications are emerging from the hype. Bayard elaborated further on the nature of workspace and how the removal of ‘silos’ is essential for effective innovation to occur between scientists, which sounded remarkably familiar to me; I realised later that it was the open structure of the Cresset office I was thinking of.
Prof. Christa Müller’s (University of Bonn) talk about purines: P2X, P2Y, P1 and P0 related receptors and enzymes, and Prof. Peter Seeberger’s (Max Planck Institute of Colloids and Interfaces) talk about the development and use of a remarkable, state-of-the-art automated glycan synthesiser for synthetic vaccine discovery got the conference off to a cracking start.
There were several themes running through the conference including: immuno-oncology, a real opportunity to tackle cancer, targeted degradation as a completely new therapeutic paradigm and the emergence of various AI strategies. Marwin Segler (Benevolent AI) showed how deep learning could be used for evaluation of millions of possible synthetic routes to a novel compound. First time disclosures are shown in table 1.
Table 1: 2D structures of first disclosures.
Risdiplam has the electrostatic hallmarks of an RNA/DNA nucleotide base interactor (a relatively electron deficient heterocycle which is then more suited to face on face interaction with nucleotide bases) in a similar manner to the fluoroquinolone antibiotics e.g., grepafloxacin (Figure 1).
Figure 1. Risdiplam structure (left) with electrostatic surface (red = positive and Blue = negative) and that of Grepafloxin (right).
GPCR talks that caught my eye are captured in table 2 and include: A MgluR2 ligand talk by Jose Cid (Jannsen), a GabbaB ligand talk by Sean Turner (AbbVie). Also, a very nice talk by Anne Valade (UCB) describing deuterium exchange as a method for identifying the allosteric ligand binding site for the dopamine D1 receptor. Finally, a first disclosure from Stefan Bäurle (Bayer) on their collaboration with Evotec.
Table 2: GPCR ligand structures.
Other ligands captured from talks that were interesting are shown in table 3. Of particular interest was the superb talk by Allan Jordan, Cancer Research UK, which possibly wins the prize for the ugliest looking validated hit.
Table 3: Ligands from other diverse talks of note.
Overall it was a successful, enjoyable and informative EFMC-ISMC symposium.