Fragment Linking Strategies for Structure-Based Drug Design

J Med Chem. 2020 Oct 22;63(20):11420-11435. doi: 10.1021/acs.jmedchem.0c00242. Epub 2020 Jun 23.

Abstract

Fragment-based drug discovery is a strategy widely used in both academia and pharmaceutical companies to generate small-molecule protein inhibitors and drug candidates. Among the approaches reported in the literature (growing, linking, and merging), the linking approach theoretically offers the opportunity to rapidly gain in binding energy. Nevertheless, this approach is poorly represented when considering the compounds currently in clinical trials. Here, we report an exhaustive view of the cases published so far in the literature, together with the methods used to identify the two initial fragments either simultaneously or successively. We review the different types of linkers published and discuss how these linkers are designed to obtain the lead compound. Mixing merging and linking methods, where the linker is duplicated from a known inhibitor, appears as an interesting strategy. To reach superadditivity, we propose to grow one of the fragments in order to minimize the distance between the two binders and then link the resulting compounds using flexible alkyl-derived linkers.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Binding Sites
  • Clinical Trials as Topic
  • Drug Approval
  • Drug Design*
  • Ligands
  • Molecular Structure
  • Nuclear Magnetic Resonance, Biomolecular
  • Pharmaceutical Preparations / chemistry*
  • Protein Binding
  • Proteins / antagonists & inhibitors*
  • Small Molecule Libraries* / chemistry
  • Small Molecule Libraries* / pharmacology
  • Structure-Activity Relationship

Substances

  • Ligands
  • Pharmaceutical Preparations
  • Proteins
  • Small Molecule Libraries