1 / 4

Influence of Protein Structure on Docking Success: A Case Study on Holo, Apo, and Modeled Conformations

This case study investigates the impact of different protein conformations (holo, apo, and modeled) on docking success in drug discovery. Using MDL Drug Data Report database and DOCK3.5, it examines how receptor structures influence ligand docking effectiveness, with a focus on 10 enzymes with known holo, apo, and modeled structures. Results indicate that holo structures yield the highest enrichment, followed by apo, while modeled structures show limitations due to poor sidechain placement. The study concludes that flexibility in binding sites enhances docking accuracy.

hollis
Télécharger la présentation

Influence of Protein Structure on Docking Success: A Case Study on Holo, Apo, and Modeled Conformations

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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

More Related