Identification of Novel Tubulin Dimer Inhibitors for Pancreatic Cancer Using an Integrated Computational Approach
Hemantha Mani Kumar Chakravarthi Chanda, Sudheer Kumar Katariintroduction:
Pancreatic cancer remains one of the most aggressive and fatal malignancies, with survival rates below 10% due to late-stage diagnosis and resistance to conventional therapies. Disruption of microtubule dynamics by targeting the α-β tubulin dimer represents a promising therapeutic strategy. This study aims to identify novel tubulin dimer inhibitors using an integrated computational drug discovery approach.
materials and methods:
A comprehensive in silico workflow was employed, combining molecular docking, density functional theory (DFT), molecular dynamics (MD) simulations, and principal component analysis (PCA). DrugBank compounds were screened to identify candidates with high binding affinity to the tubulin dimer. DFT calculations were performed to analyze electronic interactions, while MD simulations (1 µs) assessed complex stability and conformational dynamics. PCA was used to evaluate protein-ligand flexibility and adaptability.
results:
Bisphosphonate-8 and Fenoldopam were identified as potential inhibitors, with Paclitaxel used as a reference compound. Docking and binding free energy analysis revealed that Bisphosphonate-8 demonstrated nearly 2-fold higher binding affinity compared to Paclitaxel. DFT calculations confirmed strong interaction potential. MD simulations showed that Bisphosphonate-8 formed a stable complex with the tubulin dimer throughout the trajectory, while Paclitaxel exhibited significant instability. PCA confirmed the conformational adaptability and dynamic stability of Bisphosphonate-8.
discussion:
The integrated computational approach effectively identified Bisphosphonate-8 as a novel tubulin dimer inhibitor with enhanced binding efficiency, superior stability, and favorable pharmacokinetic predictions. Compared to known microtubule-targeting agents, Bisphosphonate-8 showed improved interaction and adaptability, supporting its potential as a lead compound for further investigation.
conclusion:
This study provides strong in silico evidence supporting Bisphosphonate-8 as a promising candidate for targeting the α-β tubulin dimer in pancreatic cancer. While findings are predictive and require experimental validation, the data offer a valuable foundation for future biochemical and preclinical studies aimed at developing targeted therapies for pancreatic cancer.