title: Fragment based group QSAR and molecular dynamics mechanistic studies on arylthioindole derivatives targeting the α-β interfacial site of human tubulin.
abstract: BACKGROUND
  A number of microtubule disassembly blocking agents and inhibitors of tubulin polymerization have been elements of great interest in anti-cancer therapy, some of them even entering into the clinical trials. One such class of tubulin assembly inhibitors is of arylthioindole derivatives which results in effective microtubule disorganization responsible for cell apoptosis by interacting with the colchicine binding site of the β-unit of tubulin close to the interface with the α unit. We modelled the human tubulin β unit (chain D) protein and performed docking studies to elucidate the detailed binding mode of actions associated with their inhibition. The activity enhancing structural aspects were evaluated using a fragment-based Group QSAR (G-QSAR) model and was validated statistically to determine its robustness. A combinatorial library was generated keeping the arylthioindole moiety as the template and their activities were predicted.
  
  
  RESULTS
  The G-QSAR model obtained was statistically significant with r2 value of 0.85, cross validated correlation coefficient q2 value of 0.71 and pred_r2 (r2 value for test set) value of 0.89. A high F test value of 65.76 suggests robustness of the model. Screening of the combinatorial library on the basis of predicted activity values yielded two compounds HPI (predicted pIC50 = 6.042) and MSI (predicted pIC50 = 6.001) whose interactions with the D chain of modelled human tubulin protein were evaluated in detail. A toxicity evaluation resulted in MSI being less toxic in comparison to HPI.
  
  
  CONCLUSIONS
  The study provides an insight into the crucial structural requirements and the necessary chemical substitutions required for the arylthioindole moiety to exhibit enhanced inhibitory activity against human tubulin. The two reported compounds HPI and MSI showed promising anti cancer activities and thus can be considered as potent leads against cancer. The toxicity evaluation of these compounds suggests that MSI is a promising therapeutic candidate. This study provided another stepping stone in the direction of evaluating tubulin inhibition and microtubule disassembly degeneration as viable targets for development of novel therapeutics against cancer.
authors.forename: Chetna
authors.initials: C
authors.lastname: Tyagi
authors.forename: Ankita
authors.initials: A
authors.lastname: Gupta
authors.forename: Sukriti
authors.initials: S
authors.lastname: Goyal
authors.forename: Jaspreet
authors.initials: J
authors.lastname: Dhanjal
authors.forename: Abhinav
authors.initials: A
authors.lastname: Grover
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D003078:Colchicine / Q000378:metabolism; D055808:Drug Discovery; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D055503:Protein Multimerization / Q000187:drug effects*; D020836:Protein Structure, Quaternary; D021281:Quantitative Structure-Activity Relationship; D017386:Sequence Homology, Amino Acid; D014404:Tubulin / Q000737:chemistry* / Q000378:metabolism; D050257:Tubulin Modulators / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: D007211:Indoles; D014404:Tubulin; D050257:Tubulin Modulators; D003078:Colchicine