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Structure-based pharmacophore modeling and virtual screening to identify novel inhibitors for anthrax lethal factor

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Abstract

Inhibition of anthrax lethal factor (LF) has been reported to be a potent strategy for the treatment of anthrax; however, no effective LF inhibitors are currently available. In this study, a structure-based pharmacophore model was developed based on the co-crystallized structure of anthrax LF with the active inhibitor GM6001. The best pharmacophore model (denoted as SB_Hypo1), consisting of two hydrogen bond acceptors, one hydrogen bond donor and one hydrophobic, was further validated using Gunner-Henry score method. The well-validated SB_Hypo1 was then used as a 3D-query in virtual screening to identify potential hits from NCI database. These hits were subsequently filtered by ADMET and validated by molecular docking experiments, and their binding stabilities were validated by 10-ns MD simulations. Finally, three hits were identified as potential leads based on their favorable binding interactions.

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Abbreviations

LF:

Lethal factor

PA:

Protective antigen

SBPM:

Structure-based pharmacophore model

SB_Hypo1:

Best structure-based pharmacophore model

MD:

Molecular dynamics

NCI:

National Cancer Institute

HBA:

Hydrogen-bond acceptor

HBD:

Hydrogen-bond donor

HY:

Hydrophobic

ADMET:

Absorption, distribution, metabolism, elimination and toxicology

EF:

Enrichment factor

GH:

Güner-Henry

PDB:

Protein Data Bank

PME:

Particle mesh Ewald

PBC:

Periodic boundary conditions

RMSD:

Root mean square deviation

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Acknowledgments

The authors gratefully acknowledge the financial supports from the National Science Council of Taiwan (Project number: NSC-101-2221-E-027-105-MY3), the Institute of Nuclear Energy Research of Taiwan (Project number: 1022001INER046), and National Taipei University of Technology and Taipei Medical University (Project number: NTUT-TMU-102-10).

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Authors and Affiliations

  1. Institute of Biochemical and Biomedical Engineering, National Taipei University of Technology, 1 Sec. 3 ZhongXiao E. Rd., Taipei, 10608, Taiwan

    Huang-Sheng Liao & Hsuan-Liang Liu

  2. Department of Chemical Engineering and Biotechnology, National Taipei University of Technology, 1 Sec. 3 ZhongXiao E. Rd., Taipei, 10608, Taiwan

    Hsuan-Liang Liu

  3. Chemistry Division, Institute of Nuclear Energy Research, 1000 Wunhua Rd., Longtan Township, 32546, Taoyuan County, Taiwan

    Wei-Hsi Chen

  4. School of Pharmacy, Taipei Medical University, 250 Wu-Hsing St., Taipei, 110, Taiwan

    Yih Ho

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  1. Huang-Sheng Liao
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  2. Hsuan-Liang Liu
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Correspondence to Hsuan-Liang Liu.

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Liao, HS., Liu, HL., Chen, WH. et al. Structure-based pharmacophore modeling and virtual screening to identify novel inhibitors for anthrax lethal factor. Med Chem Res 23, 3725–3732 (2014). https://doi.org/10.1007/s00044-014-0947-7

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  • DOI: https://doi.org/10.1007/s00044-014-0947-7

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