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Multi-target Fragments Display Versatile Binding Modes.

Malgorzata N Drwal1, Guillaume Bret1, Esther Kellenberger1

  • 1UMR 7200 - Laboratoire d'Innovation Thérapeutique, Université de Strasbourg, Faculté de Pharmacie, 74 Route du Rhin, 67401, Illkirch, France phone: +33 3 68 85 42 21 fax: +33 3 68 85 43 10.

Molecular Informatics
|July 11, 2017
PubMed
Summary
This summary is machine-generated.

Fragment promiscuity in drug design can yield many hits. However, this study reveals that multi-target fragments often bind in non-conserved ways, highlighting the need for structure-based modeling.

Keywords:
Fragmentsbinding mode similaritychemoinformaticsdrug designmolecular interactions and properties

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Area of Science:

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

Background:

  • Fragment-based drug design (FBDD) leverages small molecules (fragments) to identify initial binding interactions.
  • Fragment promiscuity, or the ability of a fragment to bind multiple targets, is a key concept for increasing screening hit rates.
  • Understanding how promiscuous fragments bind is crucial for optimizing drug leads.

Purpose of the Study:

  • To analyze the binding mode conservation of multi-target fragments across the Protein Data Bank (PDB).
  • To investigate the relationship between fragment properties and binding mode versatility.
  • To assess the predictive power of fragment properties for conserved versus versatile binding.

Main Methods:

  • PDB-wide analysis of fragment-protein interactions.
  • Identification and classification of multi-target fragments.
  • Comparison of binding modes and conformations for conserved and non-conserved binding.
  • Correlation analysis between fragment physicochemical properties and binding mode conservation.

Main Results:

  • The majority of analyzed multi-target fragments exhibit non-conserved binding modes, even when targeting similar proteins or binding in similar conformations.
  • Fragment properties alone are insufficient to predict whether a fragment will display a conserved or versatile binding mode.
  • Binding events are influenced by a complex interplay between fragment and protein features.

Conclusions:

  • Fragment promiscuity does not guarantee conserved binding modes, challenging simple structure-activity relationship assumptions.
  • Structure-based modeling is essential for understanding and predicting fragment binding behavior.
  • Further research should focus on the combined influence of protein and fragment characteristics on binding mode plasticity.