The first BioSoveIt Drugathon took place in July 2022 and resonated strongly with the scientific community. People from around the globe joined and contributed to the event with the aim of collaborative work on a target of interest and designing novel potential drug candidates. At the end of the 24 hour discovery session, we received over 7,000 submissions of diverse drug candidates, that were now subject to prioritization.
To keep the workflow scientifically sound and, most important, reproducible for a potential publication of the results, we docked all the 7,000+ submitted compounds into the binding site of DXPS, re-scored, and visually assessed the results with SeeSAR. Poses were checked and filtered for favorable estimated binding affinities, molecular torsions, as well as inter- and intramolecular clashes. Following this step, we checked the make-on-demand combinatorial Chemical Spaces for availability of proposed candidates.
For the availability step, we assessed the exact molecular presence within the Chemical Spaces using our SpaceMACS application. Additionally, we extracted up to 100,000 molecules per molecular motif that occupied the same subpocket of the thiamine substrate’s pyrimidine ring to expand the hunting grounds for potential binders. Consequently, we docked the 1,048,575 compounds originating from participants’ submissions and proceeded with the selection mentioned above.
Finally, a diverse set of 100 top-scoring and cherry picked compounds were discussed with our collaboration partner, HIPS, leading to the selection of 57 compounds that were ordered from Enamine on BioSolveIT’s expenses.
Unfortunately, no compound displayed inhibitory activity at DXPS in wet assays. Although the results may seem discouraging, we are also aware that setbacks are part of a drug discoverer’s life. We will work to improve the workflows for future events and are grateful for the enthusiastic research community that contributes to the projects.
We asked Prof. Dr. Anna Hirsch, the Drugathon Collaboration Partner from the HIPS Institute about her perspective:
“One has to say that DXPS represents a very difficult target due to its very hydrophilic and dynamic binding pocket . Although it may have been a little bit too ambitious as the first structure for a collaborative drug design event running only 24 hours, the compounds proposed by the community were very interesting and we would have been thrilled to see any hits. I still do see a lot of potential in such a Drugathon, because this allows a lot of people to put their perspectives into a single project. We are happy to continue the collaboration with BioSolveIT and are looking forward to the next Drugathon!”
With those encouraging words we are still highly motivated to announce the next Drugathon very soon! The concept of collaborative drug discovery is even stronger than before and the community is eager to tackle the next challenge.
With the addition of the upcoming BioSolveIT applications we are optimistic to mine for the best compounds together with the community and discover novel active scaffolds and drug candidates.