Supporting the identification of novel fragment-based positive allosteric modulators using a supervised molecular dynamics approach: A retrospective analysis considering the human A2A adenosine receptor as a key example

G. Deganutti, Veronica Salmaso , S. Moro

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Abstract

Structure-driven fragment-based (SDFB) approaches have provided efficient methods for the identification of novel drug candidates. This strategy has been largely applied in discovering several pharmacological ligand classes, including enzyme inhibitors, receptor antagonists and, more recently, also allosteric (positive and negative) modulators. Recently, Siegal and collaborators reported an interesting study, performed on a detergent-solubilized StaR adenosine A2A receptor, describing the existence of both fragment-like negative allosteric modulators (NAMs), and fragment-like positive allosteric modulators (PAMs). From this retrospective study, our results suggest that Supervised Molecular Dynamics (SuMD) simulations can support, on a reasonable time scale, the identification of fragment-like PAMs following their receptor recognition pathways and characterizing the possible allosteric binding sites.
Original languageEnglish
Article number818
Number of pages12
JournalMolecules
Volume22
Issue number5
DOIs
Publication statusPublished - 16 May 2017
Externally publishedYes

Bibliographical note

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Keywords

  • adenosine receptors
  • positive allosteric modulators
  • fragment-based approaches
  • supervised molecular dynamics

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