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Julia Salas Case Study, 3-14-06 CS379a

Julia Salas Case Study, 3-14-06 CS379a. Crystallographically determined 1. Holo: Complexed conformation Apo: Uncomplexed conformation (Homology) Modeled. Introduction. Docking often uses a single receptor structure Some algorithms allow for reception flexibility but at high cost

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Julia Salas Case Study, 3-14-06 CS379a

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

  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 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

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