1. Julia Salas Case Study, 3-14-06 CS379a
Crystallographically determined
1. Holo: Complexed conformation
Apo: Uncomplexed conformation
(Homology) Modeled
Julia Salas
Case Study,
CS379a

2. Introduction Docking often uses a single receptor structure
Some algorithms allow for reception flexibility but at high cost
For many targets, many structures are available
Most proteins don’t have published structures
5,500 out of 730,000 with known sequence (2003)
10 enzymes with known holo, apo, and homology structures
MDL Drug Data Report database molecules docked
95,000 compounds…known ligands between 0.3-1%
DOCK3.5 used, ligands were allowed flexibility
Enrichment factor was measured and compared
(# of known ligands found in ranked list) / (# expected to be found randomly)
What is the influence of protein structure on docking success?
How good does a receptor structure have to be for successful docking?

3. Results Limitations of each type of target structure:
In general, success of docking was best for holo followed by apo and lastly by modeled targets
Limitations of each type of target structure:
Holo (Best in 7 systems)
Overspecialization
Ligands with very different binding geometries were not well docked
Apo (Best in 2 systems)
Structure may be very different from ligand-bound structure
Modeled (Best in 1 system)
Sidechains could be poorly placed
Holo Active Site
Docked in Holo
Apo Active Site
Docked in Apo
EXAMPLE: Thrombin (a Serine Protease)
Apo was the best structure (24-fold over random): Slightly larger site
Holo had at best 19-fold over random: Misses some H-bonds, restricted structure

4. Conclusions Nearly all structures led to enrichment
Enrichment of at least 20-fold: 8 holo, 2 apo, 3 modeled
Holo structures are most likely to lead to useful enrichment
Except: Overspecialized Holo structures
“Promiscuous” structures are the best targets
Flexibility allowances in binding pocket lead to more accurate results
Take into account the best of both the Holo and Apo structures