Volume 4 Supplement 1

7th German Conference on Chemoinformatics: 25 CIC-Workshop

Open Access

Virtual screening for plant PARP inhibitors – what can be learned from human PARP inhibitors?

  • Peter-Paul Heym1,
  • Wolfgang Brandt1,
  • Ludger A Wessjohann1, 2 and
  • Hans-Joachim Niclas2
Journal of Cheminformatics20124(Suppl 1):O24

https://doi.org/10.1186/1758-2946-4-S1-O24

Published: 1 May 2012

The functions of Poly(ADP-ribose) polymerase enzymes (PARPs) in general are best studied based on human PARP-1 (HsPARP-1). HsPARP-1 is well investigated because pharmacological modulation of its activity modulates DNA-binding of antitumor drugs [1]. In contrast to human PARP enzymes, the exact role of PARPs in plants remains to be elucidated. Different stresses activate plant PARP enzymes to mediate DNA repair and (programmed) cell death whereas the addition of PARP inhibitors decreases the degree of cell death [2]. Therefore, the development of plant PARP inhibitors might be a way to increase the tolerance against abiotic stress.

Initial to searches in commercial databases for potential plant PARP inhibitors, a virtual screening route had to be established for human PARP-1 inhibitors. Simultaneously, every step in that procedure was applied on a plant PARP enzyme to investigate the differences of both active sites. All differences have been evaluated statistically, e.g. using receiver-operator characteristics (ROC) and power analyses. At the end of that parallel screening route, a docking threshold for Arabidopsis thaliana L. PARP-1 (AtPARP-1) could be derived by knowledge transfer from the corresponding human receptor and its inhibitors.
Figure 1

Key steps in virtual screening routes for human and Arabidopsis thaliana L. PARP-1. The results have been used to successfully apply the screening process for AtPARP-1 on a commercial database.

Knowing the differences of the human and plant screening routes, predictions of the applicability of that multi-step process on a commercial database have been explored. Finally, the developed virtual screening route has been applied to screen a commercial database for AtPARP-1 inhibitors. From 20 compounds tested so far in vitro, 13 show inhibitory effects.

Authors’ Affiliations

(1)
Leibniz-Institute for Plant Biochemistry
(2)
Agrochemical Institute Piesteritz e.V. (AIP)

References

  1. Ferraris D: Evolution of Poly(ADP-ribose) Polymerase-1 (PARP-1) Inhibitors. From Concept to Clinic. J Med Chem. 2010, 53: 4561-4584. 10.1021/jm100012m.View ArticleGoogle Scholar
  2. DeBlock M: Poly(ADP-ribose) polymerase in plants affects energy homeostasis, cell death and stress tolerance. The Plant Journal. 2005, 41: 95-106.Google Scholar

Copyright

© Heym et al; licensee BioMed Central Ltd. 2012

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.