Jump to main content
Jump to site search

Issue 8, 2015
Previous Article Next Article

Identification of new hit scaffolds by INPHARMA-guided virtual screening

Author affiliations

Abstract

Structure-based drug design (SBDD) relies on the availability of high-quality structures that describe protein–ligand interactions. INPHARMA is an NMR-based method that allows the determination of ligand binding poses to accuracy higher than 2 Å. In this work, we demonstrate that INPHARMA can be used to find novel ligand scaffolds as inhibitors of a model system protein, the cyclin-dependent kinase (Cdk-2). The workflow is given as follows: first, we determine the binding poses to Cdk-2 of six low-affinity fragments and use them to derive a structure-based pharmacophore. Two of the ligands show an unexpected binding mode, which differs from the one observed in crystal structures of other kinases. Second, we use the INPHARMA-generated pharmacophore for virtual screening of the ZINC database; one of the hit compounds is found to bind Cdk-2 in the low μM range and shows selectivity for Cdk-2 against kinases of other families. Our results demonstrate that INPHARMA is an efficient structure-based tool in solution to evolve low-affinity fragments into hit compounds.

Graphical abstract: Identification of new hit scaffolds by INPHARMA-guided virtual screening

Back to tab navigation

Supplementary files

Publication details

The article was received on 25 Mar 2015, accepted on 14 Jun 2015 and first published on 15 Jun 2015


Article type: Concise Article
DOI: 10.1039/C5MD00116A
Citation: Med. Chem. Commun., 2015,6, 1501-1507
  • Open access: Creative Commons BY license
  •   Request permissions

    Identification of new hit scaffolds by INPHARMA-guided virtual screening

    J. Sikorska, L. Codutti, L. Skjærven, B. Elshorst, R. Saez-Ameneiro, A. Angelini, P. Monecke and T. Carlomagno, Med. Chem. Commun., 2015, 6, 1501
    DOI: 10.1039/C5MD00116A

    This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. Material from this article can be used in other publications provided that the correct acknowledgement is given with the reproduced material.

    Reproduced material should be attributed as follows:

    • For reproduction of material from NJC:
      [Original citation] - Published by The Royal Society of Chemistry (RSC) on behalf of the Centre National de la Recherche Scientifique (CNRS) and the RSC.
    • For reproduction of material from PCCP:
      [Original citation] - Published by the PCCP Owner Societies.
    • For reproduction of material from PPS:
      [Original citation] - Published by The Royal Society of Chemistry (RSC) on behalf of the European Society for Photobiology, the European Photochemistry Association, and RSC.
    • For reproduction of material from all other RSC journals:
      [Original citation] - Published by The Royal Society of Chemistry.

    Information about reproducing material from RSC articles with different licences is available on our Permission Requests page.

Search articles by author

Spotlight

Advertisements