Hit picking party
Before we buy compounds, we have a hit picking party.
- this document is still in progress.
Before the party
The investigator who performed the virtual screen looks critically at the results, selecting perhaps a dozen or two interesting compounds from among the top 500. Several copies of the top 500 list are printed, sometimes with additional supporting documentation, and distributed to the participants. Check CSD data for compound pose information. The pKa of each molecule can be checked.
During the party
We take a good look at the site, and any crystallographic ligands or known experimental ligands. Think about enthalpic and entropic contributions to the binding. Think about possible water structure. Think of receptor flexibility, especially His, Gln, Asn, Ser, Tyr, Thr. Look for charged residues. Look at the surface colored by charge to look for greasy patches.
Look at one ligand at a time, and rate each compound (e.g. 1, 2, or 3 checkmarks). People speak out, making favorable and unfavorable comments about each ligand. Broken molecules are rapidly ignored.
After the party
The investigator purchases compounds as discussed and has them tested experimentally. Ideally, a report of the fate of each compound can be shared with other members of the group within a few weeks.
Epilogue
Sometimes we go through several iterations. If no hits arise, we go back to the drawing board. We try to incorporate all available information, both in the modeling, and in the judgement of the ligands.
-- John Irwin