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

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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.

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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

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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.

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Correspondence to Ashok Sharma.

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Tripathi, S., Srivastava, G., Singh, A. et al. Insight into microtubule destabilization mechanism of 3,4,5-trimethoxyphenyl indanone derivatives using molecular dynamics simulation and conformational modes analysis. J Comput Aided Mol Des 32, 559–572 (2018). https://doi.org/10.1007/s10822-018-0109-y

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