1. Knowing When to Give Up Sensible Evaluation in Virtual Screening for Drug Discovery Gwyn Skone Stephen Cameron and Irina Voiculescu

2. Virtual Screening Part of the Drug Discovery ‘Pipeline’ Identify & validate target Prepare ligand database  Filter ligands to select leads Lead result optimization Pre-clinical testing Clinical trials Approval and marketing

3. Virtual Screening

4. How is it done? Dock Target molecule Set of Ligand Conformations Set of Scored Poses Score Target molecule Ligand Pose Real

5. How is it done? Dock(T, Ls) = For each ligand L  Ls... For each possible conformation... For each considered pose... Calculate Score(T, L) N Score(T, L)=  F i (t, l) l  L atoms t  T atoms i= 1

6. How might we improve it? Function-Based Early Rejection

7. How might we improve it? Prioritized Atom Evaluation

8. How might we improve it? Red: percentage of poses abandoned; Blue: reduction in run time. Dotted lines are the unordered case.

9. How might we improve it? Result Quota Consideration Black line: run time; Bars: results by RMSD (Å): 0  Blue  1 < Green  2 < Yellow  3 < Red  4Å

10. Is there anything more positive? Use Quaternions to represent rotations

11. Is there anything more positive? Learn From Prior Experience Search Pose Pre-Selection

12. Is there anything more positive? Start in Likely Places Automatic Pocket Detection

13. end.