Skip to main content
SpringerLink
Log in

Developing novel approaches to improve binding energy estimation and virtual screening: a PARP case study

  • Original Paper
  • Published:
Journal of Molecular Modeling Aims and scope Submit manuscript

Abstract

Poly-(ADP-ribose)-polymerase (PARP) is a promising anti-cancer target as it plays a crucial role in the cellular reparation and survival mechanisms. However, the development of a robust and cost effective experimental technique to screen PARP inhibitors is still a scientific challenge owing to the difficulties in quantitative detection of the enzyme activity. In this work we demonstrate that the computational chemistry tools including molecular docking and scoring can perform on par with the experimental studies in assessing binding constants and in the recovery of active compounds in virtual screening. Using the recently introduced Lead Finder software we were able to dock a set of 142 well characterized PARP inhibitors and obtain a good correlation between the calculated and experimentally measured binding energies with the rmsd of 1.67 kcal mol−1. Additionally, fine-tuning of the energy scaling coefficients within the Lead Finder scoring function has further decreased rmsd to the value of 0.88 kcal mol−1. Moreover, we were able to reproduce the selectivity of ligand binding between the two isoforms of the enzyme-PARP1 and PARP2-suggesting that the Lead Finder software can be used to design isoform-selective inhibitors of PARP. An impressive enrichment was obtained in the virtual screening experiment, in which the mentioned set of PARP inhibitors was mixed with a commercial library of 300,000 compounds. We also demonstrate that the virtual screening performance can be significantly improved by an additional structural filtration of the docked ligand poses through detection of the crucial hydrogen bonding interactions with the enzyme.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. D’Amours D, Desnoyers S, D’Silva I, Poirier GG (1999) Poly (ADP-ribosyl) ation reactions in the regulation of nuclear functions. Biochem J 342:249–268

    Article  Google Scholar 

  2. Hassa PO, Haenni SS, Elser M, Hottiger MO (2006) Nuclear ADP-ribosylation reactions in mammalian cells: where are we today and where are we going? Microbiol Mol Biol Rev. doi:10.1128/MMBR.00040-05

  3. Hassa PO, Hottiger MO (2008) The diverse biological roles of mammalian PARPs, a small but powerful family of poly-ADP-ribose polymerases. Front Biosci. doi:10.2741/2909

  4. Jagtap P, Szabo C (2005) Poly(ADP-ribose) polymerase and the therapeutic effects of ITS inhibitors. Nat Rev Drug Discov. doi:10.1038/nrd1718

  5. Pacher P, Szabo C (2007) Role of Poly(ADP-ribose) polymerase 1 (PARP-1) in cardiovascular diseases: the therapeutic potential of PARP inhibitors. Cardiovasc Drug Rev. doi:10.1111/j.1527-3466.2007.00018.x

  6. Niedergang C, Okazaki H, Mandel P (1979) Properties of purified calf thymus poly(adenosine diphosphate ribose) polymerase. Comparison of the DNA-independent and the DNA-dependent enzyme. Eur J Biochem 102:43–57

    Article  CAS  Google Scholar 

  7. Dillon KJ, Smith GC Martin NM (2003) A flashplate assay for the identification of PARP-1 inhibitors. J Biomol Screen. doi:10.1177/1087057103008003013

  8. Decker P, Miranda EA, de Murcia G, Muller S (1999) An improved nonisotopic test to screen a large series of new inhibitor molecules of poly(ADP-ribose) polymerase activity for therapeutic applications. Clin Cancer Res 5:1169–1172

    CAS  Google Scholar 

  9. Brown JA, Marala RB (2002) Development of a high-throughput screening-amenable assay for human poly(ADP-ribose) polymerase inhibitors. J Pharmacol Toxicol Method. doi:10.1016/S1056-8719(02)00223-X

  10. Lee S, Koo HN, Lee BH (2005) Development of a miniaturized assay for the high-throughput screening program for poly(ADP-ribose) polymerase-1. Methods Find Exp Clin Pharmacol. doi:10.1358/mf.2005.27.9.939334

  11. Putt KS, Hergenrother PJ (2004) An enzymatic assay for poly(ADP-ribose) polymerase-1 (PARP-1) via the chemical quantitation of NAD+: application to the high-throughput screening of small molecules as potential inhibitors. Anal Biochem. doi:10.1016/j.ab.2003.11.015

  12. Perkins E, Sun D, Nguyen A et al. (2001) Novel inhibitors of poly(ADP-ribose) polymerase/PARP1 and PARP2 identified using a cell-based screen in yeast. Cancer Res 61:4175–4183

    CAS  Google Scholar 

  13. Costantino G, Macchiarulo A, Camaioni E, Pellicciari R (2001) Modeling of poly(ADP-ribose)POLYMERASE (PARP) inhibitors. Docking of ligands and quantitative structure-activity relationship analysis. J Med Chem. doi:10.1021/jm010116l

  14. Bellocchi D, Macchiarulo A, Costantino G, Pellicciari R (2005) Docking studies on PARP-1 inhibitors: insights into the role of a binding pocket water molecule. Bioorg Med Chem. doi:10.1016/j.bmc.2004.11.024

  15. Stroganov OV, Novikov FN, Stroylov VS et al. (2008) Lead finder: an approach to improve accuracy of protein-ligand docking, binding energy estimation, and virtual screening. J Chem Inf Model. doi:10.1021/ci800166p

  16. Ishida J, Yamamoto H, Kido Y et al. (2006) Discovery of potent and selective PARP-1 and PARP-2 inhibitors:SBDD analysis via a combination of X-ray structural study and homology modeling. Bioorg Med Chem. doi:0.1016/j.bmc.2005.09.061

  17. Dunn D, Husten J, Ator MA and Chatterjee S (2007) Novel poly(ADP-ribose) polymerase-1 inhibitors. Bioorg Med Chem Lett. doi:10.1016/j.bmcl.2006.10.010

  18. Hattori K, Kido Y, Yamamoto H et al. (2007) Rational design of conformationally restricted quinazolinone inhibitors of poly(ADP-ribose)polymerase. Bioorg Med Chem Lett. doi:10.1016/j.bmcl.2007.07.091

  19. Hattori K, Kido Y, Yamamoto H et al. (2004) Rational approaches to discovery of orally active and brain-penetrable quinazolinone inhibitors of poly(ADP-ribose)polymerase. J Med Chem. doi:10.1021/jm0499256

  20. PARP ligands (2009) BioMolTech Corp, Toronto. http://www.biomoltech.com/downloads/papers/supp_inf_parp_ligands_2008_12.zip. Accessed 25 Jan 2008

  21. Simonin F, Pochj O, Delarue M, de Murcia G (1993) Identification of potential active-site residues in the human poly(ADP-ribose) polymerase. J Biol Chem 268:8529–8535

    CAS  Google Scholar 

  22. STK library (2007) Vitas-M Laboratory, Moscow. http://www.vitasmlab.com/compound-libraries-2.htm. Accessed 25 Jan 2008

  23. Jain AN, Nicholls A (2008) Recommendations for evaluation of computational methods. J Comput Aided Mol Des. doi:10.1007/s10822-008-9196-5

  24. Ame JC, Rolli V, Schreiber V et al. (1999) PARP-2, a novel mammalian DNA damage-dependent Poly(ADP-ribose) polymerase. J Biol Chem 274:17860–17868

    Article  CAS  Google Scholar 

Download references

Acknowledgments

Our special thanks to Prof. Viktor Gergel and Alexander Grishagin, the Center of Supercomputer Technologies of the N.I. Lobacevsky State University of Nizhni Novgorod, for our access to the high-performance computing cluster (Nizhni Novgorod segment of the SKIF-grid program).

Author information

Authors and Affiliations

  1. MolTech Ltd, 119992, Moscow, Leninskie gory, 1/75A, Russia

    Fedor N. Novikov, Oleg V. Stroganov & Ghermes G. Chilov

  2. Department of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119992, Moscow, Leninskie gory, 1/73, Russia

    Fedor N. Novikov & Viktor S. Stroylov

  3. Belozersky Institute of Physicochemical Biology, Lomonosov Moscow State University, 119992, Moscow, Acad. Khokhlov st. 6, Russia

    Oleg V. Stroganov & Ghermes G. Chilov

  4. BioMolTech Corp, 226 York Mills Rd, Toronto, Ontario, M2L 1 L1, Canada

    Val Kulkov

Authors
  1. Fedor N. Novikov
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Viktor S. Stroylov
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Oleg V. Stroganov
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Val Kulkov
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ghermes G. Chilov
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ghermes G. Chilov.

Electronic supplementary materials

Below is the link to the electronic supplementary material.

ESM 1

(DOC 548 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Novikov, F.N., Stroylov, V.S., Stroganov, O.V. et al. Developing novel approaches to improve binding energy estimation and virtual screening: a PARP case study. J Mol Model 15, 1337–1347 (2009). https://doi.org/10.1007/s00894-009-0497-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00894-009-0497-y

Keywords

Search

Navigation