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Cited by 668Computational Drug Discovery MethodsSynthesis and Characterization of Heterocyclic Compoundsvaccines and immunoinformatics approaches

Validation of Molecular Docking Programs for Virtual Screening against Dihydropteroate Synthase

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Hevener, Kirk E., Zhao, Wei, Ball, David M., Babaoglu, Kerim, Qi, Jianjun, White, Stephen W., Lee, Richard E.·2009·Journal of Chemical Information and Modeling
DOI 10.1021/ci800293nPMC PMC2788795
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Abstract

Dihydropteroate synthase (DHPS) is the target of the sulfonamide class of antibiotics and has been a validated antibacterial drug target for nearly 70 years. The sulfonamides target the p-aminobenzoic acid (pABA) binding site of DHPS and interfere with folate biosynthesis and ultimately prevent bacterial replication. However, widespread bacterial resistance to these drugs has severely limited their effectiveness. This study explores the second and more highly conserved pterin binding site of DHPS as an alternative approach to developing novel antibiotics that avoid resistance. In this study, five commonly used docking programs, FlexX, Surflex, Glide, GOLD, and DOCK, and nine scoring functions, were evaluated for their ability to rank-order potential lead compounds for an extensive virtual screening study of the pterin binding site of B. anthracis DHPS. Their performance in ligand docking and scoring was judged by their ability to reproduce a known inhibitor conformation and to efficiently detect known active compounds seeded into three separate decoy sets. Two other metrics were used to assess performance; enrichment at 1% and 2% and Receiver Operating Characteristic (ROC) curves. The effectiveness of postdocking relaxation prior to rescoring and consensus scoring were also evaluated. Finally, we have developed a straightforward statistical method of including the inhibition constants of the known active compounds when analyzing enrichment results to more accurately assess scoring performance, which we call the 'sum of the sum of log rank' or SSLR. Of the docking and scoring functions evaluated, Surflex with Surflex-Score and Glide with GlideScore were the best overall performers for use in virtual screening against the DHPS target, with neither combination showing statistically significant superiority over the other in enrichment studies or pose selection. Postdocking ligand relaxation and consensus scoring did not improve overall enrichment.

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  • The molecular docking pose was validated by aligning the X-ray bioactive conformer with the best-fitted pose, and validation was considered satisfactory when the RMSD was smaller than 2.0 Å relative to the crystallographic pose of the respective ligand.

    “The ideal pose was validated by aligning the X-ray bioactive conformer with the best-fitted pose of the same compound for the enzyme. The perfect pose of each molecule was selected according to the energy score, and the validation was considered satisfactory when the RMSD was smaller than 2.0 Å with respect to the crystallographic pose of the respective ligand [34].”

    From The Valorization of Spent Coffee Ground Extract as a Prospective Insecticidal Agent against Some Main Key Pests of Phaseolus vulgaris in the Laboratory and Field (2022) · cites this paper as [34]

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Authors
Hevener, K. E., Zhao, W., Ball, D. M., Babaoglu, K., Qi, J., White, S. W., & Lee, R. E.
Affiliations
  • St. Jude Children's Research Hospital (US)
  • Departments of Pharmaceutical Sciences and Molecular Sciences, University of Tennessee Health Science Center, Memphis, Tennessee 38163, and
ORCID
Venue
Journal of Chemical Information and Modeling
Publisher
American Chemical Society (ACS)
Published
2009-01-27
Volume
49
Issue
2
Pages
444-460
ISSN
  • 1549-9596 (ISSN-L)
  • 1549-960X
DOI
10.1021/ci800293n
PMC
PMC2788795
OpenAlex
W2036927874
Cited by
668
References
2
Citations by year
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FWCI
7.81
Type
journal article
Language
en
Open access
Locations
  • Journal of Chemical Information and Modeling (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • American Foundation for Pharmaceutical Education
  • American Lebanese Syrian Associated Charities
  • National Institutes of Health
  • National Institute of Allergy and Infectious Diseases (AI060953, R21AI060953, R01AI070721, AI070721)
Topics
  • Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
  • Physical Sciences › Chemistry › Organic Chemistry › Synthesis and Characterization of Heterocyclic Compounds
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
Keywords
dihydropteroate synthase, virtual screening, sulfonamide resistance, Bacillus anthracis, antibiotic targets, docking scoring functions, enrichment analysis, consensus scoring, glides, FlexX, gold, dock
MeSH terms
Bacillus anthracis, Dihydropteroate Synthase, Models, Molecular, Protein Conformation, ROC Curve

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