Identification of Essential 2D and 3D Chemical Features for Discovery of the Novel Tubulin Polymerization Inhibitors
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.
Document Type: Research Article
Publication date: May 1, 2019
This article was made available online on June 26, 2019 as a Fast Track article with title: "Identification of Essential 2D and 3D Chemical Features for Discovery of the Novel Tubulin Polymerization Inhibitors".