Jove
Visualize
Contact Us
JoVE
x logofacebook logolinkedin logoyoutube logo
ABOUT JoVE
OverviewLeadershipBlogJoVE Help Center
AUTHORS
Publishing ProcessEditorial BoardScope & PoliciesPeer ReviewFAQSubmit
LIBRARIANS
TestimonialsSubscriptionsAccessResourcesLibrary Advisory BoardFAQ
RESEARCH
JoVE JournalMethods CollectionsJoVE Encyclopedia of ExperimentsArchive
EDUCATION
JoVE CoreJoVE BusinessJoVE Science EducationJoVE Lab ManualFaculty Resource CenterFaculty Site
Terms & Conditions of Use
Privacy Policy
Policies

Related Experiment Videos

Flexible ligand docking using conformational ensembles

D M Lorber1, B K Shoichet

  • 1Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School, Chicago, Illinois 60611-3008, USA.

Protein Science : a Publication of the Protein Society
|May 6, 1998
PubMed
Summary
This summary is machine-generated.

Related Concept Videos

You might also read

Related Articles

Articles linked to this work by shared authors, journal, and citation graph.

Sort by
Same author

A Molecular Basis for Innovation in Drug Excipients.

Clinical pharmacology and therapeutics·2016
Same author

Structures of ceftazidime and its transition-state analogue in complex with AmpC beta-lactamase: implications for resistance mutations and inhibitor design.

Biochemistry·2001
Same author

Inhibition of AmpC beta-lactamase through a destabilizing interaction in the active site.

Biochemistry·2001
Same author

Structure-based design and in-parallel synthesis of inhibitors of AmpC beta-lactamase.

Chemistry & biology·2001
Same author

Interaction energies between beta-lactam antibiotics and E. coli penicillin-binding protein 5 by reversible thermal denaturation.

Protein science : a publication of the Protein Society·2001
Same author

Energetic, structural, and antimicrobial analyses of beta-lactam side chain recognition by beta-lactamases.

Chemistry & biology·2001
Same journal

Macromolecular crowding inhibits degradation of alpha-synuclein amyloid fibrils induced by cathepsins and MMP9.

Protein science : a publication of the Protein Society·2026
Same journal

Sequence-encoded differences in the conformational ensembles of CITED transcriptional activation domains impact coactivator binding.

Protein science : a publication of the Protein Society·2026
Same journal

The phospholipid biosynthesis enzyme PlsB contains three distinct domains for membrane association, lysophosphatidic acid synthesis, and dimerization.

Protein science : a publication of the Protein Society·2026
Same journal

Structural basis of ligand selectivity in FAD/NAD(P)H-dependent dehydrogenases: insights from trypanothione reductase and type II NADH dehydrogenase.

Protein science : a publication of the Protein Society·2026
Same journal

Achieving protease substrate-specific inhibition by mAb dual functional selections.

Protein science : a publication of the Protein Society·2026
Same journal

How important are quantum mechanical effects in controlling biological functions: Enzymes, electron transfer and bird navigation.

Protein science : a publication of the Protein Society·2026
See all related articles

This study introduces a faster molecular docking method by docking ligand ensembles, not single conformations. This approach significantly speeds up drug discovery by efficiently screening millions of molecular structures.

Area of Science:

  • Computational Chemistry
  • Structural Biology
  • Drug Discovery

Background:

  • Molecular docking is crucial for modeling biological functions and identifying potential drug ligands.
  • A key limitation in current docking algorithms is the accurate handling of molecular flexibility.
  • Existing methods often struggle to efficiently incorporate the dynamic nature of molecules during docking simulations.

Purpose of the Study:

  • To enhance molecular docking by developing a method that rapidly fits multiple ligand conformations simultaneously.
  • To improve the efficiency and accuracy of identifying potential drug candidates by accounting for molecular flexibility.
  • To accelerate the drug discovery process through a more effective ligand docking strategy.

Main Methods:

  • Modified the DOCK rigid body program to enable rapid fitting of multiple ligand conformations as an ensemble.

Related Experiment Videos

  • Pre-calculated ligand conformations in a common reference frame, sharing a rigid fragment for efficient ensemble docking.
  • Tested the ligand ensemble docking method on organic ligand-protein and protein-protein systems, using both bound and unbound receptor conformations.

    • Main Results:

    • The ligand ensemble method successfully identified ligand conformations similar to those found in X-ray crystal structures (RMS values typically < 1.5 Å).
    • Screening of known inhibitor databases for dihydrofolate reductase and thymidylate synthase identified known inhibitors and substrates in experimentally relevant conformations.
    • Achieved a 100-fold increase in speed compared to single-conformation docking, enabling the screening of over 34 million conformations in 1-4 CPU days.

    Conclusions:

    • The ligand ensemble docking method effectively models molecular flexibility and accelerates the identification of potential drug candidates.
    • This approach offers a significant speed improvement for virtual screening, making it practical for large-scale database analysis.
    • The method demonstrates utility in both structure-based drug design and the discovery of novel inhibitors.