IN SILICO ANALYSIS OF STRUCTURAL REQUIREMENTS FOR THIOPHENE DERIVATIVES AGAINST POLO LIKE KINASE-1 (PLK1)
Keywords:
Anti-mitotics, Thiophene derivatives against PLK1, 3D-QSAR, CoMFA, CoMSIA, Molecular DockingAbstract
Objective: Development of anti-mitotic drugs for chemotherapy of cancer has been one of the main focuses of research in 21st century. Present work aims to study the structural requirements of thiophene derivatives against PLK1 as a target for designing novel strategies for cancer chemoprevention. To understand the structural requirements that will lead to enhanced inhibitory potencies, we have carried out 3D-QSAR (quantitative structure-activity relationship) studies on a series of thiophene derivatives as PLK1 receptor inhibitors.
Methods: CoMFA, CoMSIA and molecular docking studies were performed on a series of thiophene derivatives as PLK1 receptor inhibitors using Sybyl 6.7.
Results: We have successfully derived statistically significant model from 100 thiophene derivatives and validated, it against an external test set of 34 compounds and 66 molecules used in the training set. The CoMFA model yielded q2-0.845, r2-0.978. While the CoMSIA model yielded q2-0.804, r2-0.968. The predictive ability of these models supported by docking studies; produced better docking scores and binding affinity to the specified target polo like kinase1 (3THB) and moreover, the 3D QSAR model used for suggesting the next-generation lead analogues.
Conclusion: 3D-QSAR has been established for a series of Polo like Kinase1 (PLK1) inhibitors employing the most widely used techniques CoMFA and CoMSIA. The conclusions derived from both models are similar and reliable. Docking studies are also performed to obtain the bioactive confirmations for the whole data-set. The obtained 3D contour maps along with the docking results provided a rational clue for the design of more favorable anti-mitotic agents. Overall, the structural modifications of the lead molecule have achieved to improve selective PLK1 inhibitory activity.
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