BACKGROUND: A number of microtubule disassembly blocking agents and inhibitors of tubulin polymerization have been elements of great interest in anti- @entity5 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 @entity3812 binding site of the b-unit of tubulin close to the interface with the a unit. We modelled the @entity1 tubulin b 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 @entity10076 (predicted pIC50 = 6.042) and @entity17798 (predicted pIC50 = 6.001) whose interactions with the D chain of modelled @entity1 tubulin protein were evaluated in detail. A @entity137 evaluation resulted in @entity17798 being less toxic in comparison to @entity10076 . 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 @entity1 tubulin. The two reported compounds @entity10076 and @entity17798 showed promising anti @entity5 activities and thus can be considered as potent leads against @entity5 . The @entity137 evaluation of these compounds suggests that @entity17798 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 @entity5 .

Fragment based group QSAR and molecular dynamics mechanistic studies on arylthioindole derivatives targeting the a-b interfacial site of XXXX tubulin.

@entity1 :: ('9606', 'Species') :: ['human'] @entity17798 :: ('5928', 'Gene') :: ['MSI'] @entity137 :: ('MESH:D064420', 'Disease') :: ['toxicity'] @entity5 :: ('MESH:D009369', 'Disease') :: ['cancer'] @entity10076 :: ('MESH:C538384', 'Disease') :: ['HPI'] @entity3812 :: ('MESH:D003078', 'Chemical') :: ['colchicine']
@entity1 :: (9606,Species) :: ['human']
