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FLEXS: a method for fast flexible ligand superposition

C Lemmen1, T Lengauer, G Klebe

  • 1Institute for Algorithms and Scientific Computing (SCAI), German National Research Center for Information Technology (GMD), Schlobeta Birlinghoven, 53754 Sankt Augustin, Germany. Lemmen@gmd.de

Journal of Medicinal Chemistry
|November 7, 1998
PubMed
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We developed FLEXS, an automated method for structurally aligning flexible ligands to rigid references, aiding rational drug design. FLEXS accurately predicts binding geometries and ranks ligands, outperforming 2D similarity methods in virtual screening.

Area of Science:

  • Computational chemistry
  • Structural bioinformatics
  • Drug discovery

Background:

  • Rational drug design requires accurate structural alignment of ligands to predict binding geometry and similarity.
  • Existing methods for ligand superposition are crucial for 3D QSAR, pharmacophore hypothesis generation, and receptor modeling.

Purpose of the Study:

  • To present FLEXS, an automated method for structurally superimposing pairs of ligands to approximate binding site geometry.
  • To evaluate FLEXS's speed and accuracy for virtual ligand screening and its performance against experimental data.

Main Methods:

  • FLEXS employs an incremental construction procedure, partitioning molecules into fragments and iteratively adding them.
  • Ligand flexibility is incorporated by allowing fragments to adopt discrete conformations.

Related Experiment Videos

  • The method uses a rigid reference ligand and a flexible query ligand.

    • Main Results:

    • FLEXS achieves a mean computing time of approximately 1.5 minutes per test case on a standard workstation.
    • In virtual screening for fibrinogen receptor antagonists, FLEXS retrieved active ligands within the top 20 hits and identified novel candidates.
    • Validation against experimental data showed root-mean-square deviations below 1.5 Å for over half of the test set, particularly for small- to medium-sized molecules.

    Conclusions:

    • FLEXS is a fast and accurate tool for automated ligand superposition, suitable for virtual screening in drug discovery.
    • The method demonstrates superiority over 2D fingerprint similarity techniques for retrieval tasks.
    • While effective for small- to medium-sized ligands, FLEXS has limitations with very large molecules or complex binding modes.