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Journal of Computer-Aided Molecular Design

, Volume 32, Issue 4, pp 559–572 | Cite as

Insight into microtubule destabilization mechanism of 3,4,5-trimethoxyphenyl indanone derivatives using molecular dynamics simulation and conformational modes analysis

  • Shubhandra Tripathi
  • Gaurava Srivastava
  • Aastha Singh
  • A. P. Prakasham
  • Arvind S. Negi
  • Ashok Sharma
Article

Abstract

Colchicine site inhibitors are microtubule destabilizers having promising role in cancer therapeutics. In the current study, four such indanone derivatives (t1, t9, t14 and t17) with 3,4,5-trimethoxyphenyl fragment (ring A) and showing significant microtubule destabilization property have been explored. The interaction mechanism and conformational modes triggered by binding of these indanone derivatives and combretastatin at colchicine binding site (CBS) of αβ-tubulin dimer were studied using molecular dynamics (MD) simulation, principle component analysis and free energy landscape analysis. In the MD results, t1 showed binding similar to colchicine interacting in the deep hydrophobic core at the CBS. While t9, t14 and t17 showed binding conformation similar to combretastatin, with ring A superficially binding at the CBS. Results demonstrated that ring A played a vital role in binding via hydrophobic interactions and got anchored between the S8 and S9 sheets, H8 helix and T7 loop at the CBS. Conformational modes study revealed that twisting and bending conformational motions (as found in the apo system) were nearly absent in the ligand bound systems. Absence of twisting motion might causes loss of lateral contacts in microtubule, thus promoting microtubule destabilization. This study provides detailed account of microtubule destabilization mechanism by indanone ligands and combretastatin, and would be helpful for designing microtubule destabilizers with higher activity.

Keywords

Microtubule αβ-Tubulin dimer Molecular dynamics simulation Principle component analysis Free energy landscape analysis 

Abbreviations

MD

Molecular dynamics

Colch

Colchicine

CSI

Colchicine site inhibitor

CBS

Colchicine binding site

GTP/GDP

Guanosine tri/di-phosphate

Combr

Combretastatin

MMPBSA

Molecular mechanics Poisson Boltzmann surface area

PCA

Principle component analysis

PC

Principle component

FEL

Free energy landscape

RMSD

Root mean square deviation

RMSF

Root mean square fluctuation

Notes

Acknowledgements

Shubhandra Tripathi is thankful to CSIR, New Delhi for Senior Research Fellowship. Gaurava Srivastava is thankful to ICMR, New Delhi for Senior Research Fellowship. Financial support from BSC0203 is also acknowledged. Authors are thankful to CSIR-4pi, Bengaluru for providing High Performance Computing facility.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

10822_2018_109_MOESM1_ESM.zip (26.4 mb)
Supplementary material 1 (ZIP 26995 KB)

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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Biotechnology DivisionCSIR-Central Institute of Medicinal and Aromatic Plants (CSIR-CIMAP)LucknowIndia
  2. 2.Chemical Science DivisionCSIR-Central Institute of Medicinal and Aromatic Plants (CSIR-CIMAP)LucknowIndia
  3. 3.Department of ChemistryIITMumbaiIndia

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