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Validation of molecular docking programs for virtual screening against dihydropteroate synthase
Kirk E Hevener1, Wei Zhao, David M Ball
1Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
Journal of Chemical Information and Modeling
|May 13, 2009
Summary
This study evaluated docking programs for identifying new antibiotics targeting the pterin binding site of dihydropteroate synthase (DHPS). Surflex and Glide demonstrated the best performance for virtual screening against this drug target.
Area of Science:
- Microbiology
- Drug Discovery
- Computational Chemistry
Background:
- Dihydropteroate synthase (DHPS) is a key target for sulfonamide antibiotics, crucial for bacterial folate biosynthesis.
- Bacterial resistance to existing sulfonamides necessitates exploration of alternative drug targets and strategies.
- The pterin binding site of DHPS presents a conserved and promising target for novel antibiotic development.
Purpose of the Study:
- To evaluate the performance of five docking programs and nine scoring functions for virtual screening of the DHPS pterin binding site.
- To identify optimal computational methods for discovering novel antibacterial compounds that circumvent existing resistance mechanisms.
- To assess the utility of postdocking relaxation and consensus scoring in enhancing virtual screening accuracy.
Main Methods:
- Comparative analysis of docking programs (FlexX, Surflex, Glide, GOLD, DOCK) and scoring functions.
- Validation using known inhibitor conformations and seeded active compounds in decoy sets.
- Performance metrics included enrichment at 1% and 2%, Receiver Operating Characteristic (ROC) curves, and a novel statistical method (SSLR).
Main Results:
- Surflex with Surflex-Score and Glide with GlideScore emerged as the top-performing docking and scoring combinations.
- Neither of the best-performing combinations showed statistically significant superiority in enrichment or pose selection.
- Postdocking ligand relaxation and consensus scoring did not yield significant improvements in overall enrichment.
Conclusions:
- Surflex and Glide are recommended for virtual screening of the DHPS pterin binding site for novel antibiotic discovery.
- The study provides a robust evaluation framework for computational drug discovery against validated antibacterial targets.
- Further research may focus on refining these methods or exploring other DHPS binding sites to combat antibiotic resistance.
