Journal of Computer-Aided Molecular Design

, Volume 24, Issue 1, pp 1–15 | Cite as

Molecular docking and QSAR of aplyronine A and analogues: potent inhibitors of actin

  • Abrar Hussain
  • James L. Melville
  • Jonathan D. Hirst
Article

Abstract

Actin-binding natural products have been identified as a potential basis for the design of cancer therapeutic agents. We report flexible docking and QSAR studies on aplyronine A analogues. Our findings show the macrolide ‘tail’ to be fundamental for the depolymerisation effect of actin-binding macrolides and that it is the tail which forms the initial interaction with the actin rather than the macrocycle, as previously believed. Docking energy scores for the compounds were highly correlated with actin depolymerisation activity. The 3D-QSAR models were predictive, with the best model giving a q 2 value of 0.85 and a r 2 of 0.94. Results from the docking simulations and the interpretation from QSAR “coeff*stdev” contour maps provide insight into the binding mechanism of each analogue and highlight key features that influence depolymerisation activity. The results herein may aid the design of a putative set of analogues that can help produce efficacious and tolerable anti-tumour agents. Finally, using the best QSAR model, we have also made genuine predictions for an independent set of recently reported aplyronine analogues.

Keywords

Aplyronine A Macrolides F-actin depolymerisation 3D-QSAR AutoDock 

Notes

Acknowledgments

We thank Craig Bruce for advice and useful discussions.

Supplementary material

10822_2009_9307_MOESM1_ESM.pdf (62 kb)
PDF (61 KB)

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Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  • Abrar Hussain
    • 1
  • James L. Melville
    • 2
  • Jonathan D. Hirst
    • 1
  1. 1.School of ChemistryUniversity of NottinghamNottinghamUK
  2. 2.Cresset BioMolecular Discovery Ltd., BioPark HertfordshireHertfordshireUK

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