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Virtual screening and scaffold hopping based on GRID molecular interaction fields.

Marie M Ahlström1, Marianne Ridderström, Kristina Luthman

  • 1DMPK & BAC Department, AstraZeneca R&D Mölndal, SE-431 81 Mölndal, Sweden. marie.m.ahlstrom@astrazeneca.com

Journal of Chemical Information and Modeling
|September 27, 2005
PubMed
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Structure-based drug design strategies using GRID molecular interaction fields (MIFs) efficiently identified thrombin inhibitors. This approach achieved 80% retrieval and enabled scaffold hopping, aiding medicinal chemists in selecting core structures.

Area of Science:

  • Computational chemistry and cheminformatics
  • Drug discovery and medicinal chemistry
  • Structural biology

Background:

  • Thrombin is a key enzyme in blood coagulation, making it a target for drug development.
  • Abundant structural data and inhibitor information exist for thrombin.
  • Structure-based design requires effective methods for identifying potential drug candidates and scaffolds.

Purpose of the Study:

  • To develop and validate strategies for structure-based drug design using GRID molecular interaction fields (MIFs).
  • To derive pharmacophoric representations of proteins and enable scaffold hopping for drug discovery.
  • To assess the efficiency of virtual screening and scaffold selection methodologies.

Main Methods:

  • Utilized GRID molecular interaction fields (MIFs) to generate pharmacophore models and scaffold interaction patterns.

Related Experiment Videos

  • Developed a virtual screening methodology searching a 3D multiconformation database spiked with known thrombin inhibitors.
  • Implemented a scaffold hopping methodology by parameterizing and searching a database of scaffolds against a template.

    • Main Results:

    • Virtual screening identified 80% of known thrombin inhibitors within 5% of the database, achieving 15-fold enrichment.
    • Scaffold hopping successfully identified known thrombin scaffolds from a searchable database.
    • Docking of newly built molecules confirmed binding patterns similar to co-complexed ligands.

    Conclusions:

    • GRID MIFs provide a robust method for structure-based design and pharmacophore derivation.
    • The developed virtual screening and scaffold hopping methods are efficient tools for drug discovery.
    • This approach facilitates the selection of interchangeable scaffolds while preserving binding properties, aiding medicinal chemists.