Conduct ligand-protein docking

A long-standing customer of Cresset Discovery asked us to identify new compounds that could be active at their protein target. We conducted ligand-protein docking to narrow down their 50k compound library to the best 1.5k compounds. The cost of the consulting project plus the chemistry for 1.5k compounds was about 20% of what it would have cost to buy and screen the entire 50k library.

Ligand-protein docking can be an excellent way to build up knowledge about the binding pocket. It can also form the basis for a virtual screen to identify new active compounds.

Cresset Discovery had been working with this customer on a particular ligand for some time, but there was very little information available about the protein target. There were homologues in the literature, but they were distantly related and nothing very similar had been crystallized.

Detailed preparatory work to model the protein active site

It was necessary to do a lot of modeling work to build up the relationship between the human target and the distantly related proteins available from the literature. We built sequence alignments and compared them, enabling us to build up 3D models of the target and its interaction with the ligand.

Some mutagenesis data was available on the known ligands, so we were able to use this to refine the 3D models and check that the correct residues were in the right places on the active site. This enabled us to define the active site for the ligands. We went on to calculate the energies for the protein-ligand interactions to make sure we had identified poses that made sense.

This was a complex system that required a great deal of protein preparation. This preparatory work was essential for successful docking and required expert knowledge, experience and skill.

Docking and virtual screening using different scenarios

At the end of this process we had a good model of the protein-ligand system. The next step was to remove the ligand and carry out docking.

Docking was first tested on the molecules that were known to bind to the target. This resulted in excellent retrieval rates, showing that the model would also be able to retrieve new compounds.

There were a number of different binding sites on the protein so we decided to carry out the virtual screening using different scenarios for the protein. We:

  • Kept the ligand intact in the binding site
  • Removed the ligand completely
  • Looked at partly bound situations and un-bound situations for each of the binding sites.

The customer provided us with a set of 50k ligands and we docked each of these against the binding pockets. A docking scoring system was used to rank the top 2k compounds from each of the screens.

Analyzing the results and compiling a purchasing list

The top 2k compounds from the four screens were analysed in detail. We visualized every one of the top 2k compounds and looked at each of the docking poses. The docking gave us good geometries for the ligands and we used Cresset software to check that the electrostatics made sense. Any compounds that were unlikely to bind well were rejected.

A final, ranked list was provided to the customer with a very high degree of confidence that it included compounds that were active at the protein target. They were able to procure about 75% of the compounds from the hit list, giving them a final set of 1.5k compounds to test.

An incredible saving in time and money

Carrying out virtual screening to focus the library in this way represented an incredible saving in time and money for our customer. The alternative approach would have been to buy and test the whole 50k compound set. Not only would the customer have needed to purchase all of the compounds, but also shipped them, stored them, plated them, screened them, and then they would still have to analyse the results.

The estimated cost of doing this for all 50k compounds would have been about five times the cost of the combined tasks of the Cresset Discovery project plus buying and testing 1.5k compounds.

Cost of {buying and testing 50k compounds} =5X Cost of {Cresset Discovery project + buying and testing 1.5k hit list}.


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Scientists collaborating on small molecule discovery projects