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

Autor:	A. P. Prakasham, Arvind S. Negi, Ashok Sharma, Shubhandra Tripathi, Gaurava Srivastava, Aastha Singh
Přispěvatelé:	Supramolecular Chemistry & Catalysis
Rok vydání:	2018
Předmět:	0301 basic medicine AMBER FORCE-FIELD TUBULIN POLYMERIZATION Dimer Molecular Conformation Free energy landscape analysis Microtubule Ligands Microtubules Principle component analysis Hydrophobic effect Structure-Activity Relationship 03 medical and health sciences Molecular dynamics chemistry.chemical_compound Isomerism SDG 3 - Good Health and Well-being Bibenzyls Molecular dynamics simulation Drug Discovery ANTICANCER ACTIVITY αβ-Tubulin dimer Physical and Theoretical Chemistry AGENTS Combretastatin Principal Component Analysis Binding Sites COLCHICINE Ligand Energy landscape Tubulin Modulators Computer Science Applications BINDING-SITE 030104 developmental biology chemistry alpha ss-Tubulin dimer THERMOSTABILITY Indans Helix Biophysics Thermodynamics INHIBITORS RESISTANCE Protein Binding
Zdroj:	Journal of Computer-Aided Molecular Design, 32(4), 559-572. Springer
ISSN:	1573-4951 0920-654X
DOI:	10.1007/s10822-018-0109-y
Popis:	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 alpha beta-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.
Databáze:	OpenAIRE
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