Background: Tubulin polymerization inhibitors interfere with microtubule assembly and
their functions lead to mitotic arrest, therefore they are attractive target for design and development of
novel anticancer compounds.
Objective: The proposed novel and effective structures following the use of three-dimensionalquantitative
structure activity relationship (3D-QSAR) pharmacophore based virtual screening clearly
demonstrate the high efficiency of this method in modern drug discovery.
Methods: Combined computational approach was applied to extract the essential 2D and 3D features
requirements for higher activity as well as identify new anti-tubulin agents.
Results: The best quantitative pharmacophore model, Hypo1, exhibited good correlation of 0.943
(RMSD=1.019) and excellent predictive power in the training set compounds. Generated model
AHHHR, was well mapped to colchicine site and three-dimensional spatial arrangement of their features
were in good agreement with the vital interactions in the active site. Total prediction accuracy
(0.92 for training set and 0.86 for test set), enrichment factor (4.2 for training set and 4.5 for test set)
and the area under the ROC curve (0.86 for training set and 0.94 for the test set), the developed model
using Extended Class FingerPrints of maximum diameter 4 (ECFP_4) was chosen as the best model.
Conclusion: Developed computational platform provided a better understanding of requirement features
for colchicine site inhibitors and we believe the results of this study might be useful for the rational
design and optimization of new inhibitors.