Ensemble Pharmacophore Meets Molecular Docking: A Novel Screening Approach for the Identification of B-Raf Kinase Inhibitors

Abstract

In US about 106110 diagnosed as melanomas, 7,180 people expected to die due to melanoma. B-RAF is a cytoplasmic serine - threonine kinase that is found in a mutated form in melanoma and colorectal cancer. Sorafenib was initially introduced as a B-RAF inhibitor in melanoma. Hence it is taken as a pivot molecule in our study. Four potent B-Raf kinase inhibitors (Sorafenib, Regorafenib, N-desmethyl sorafenib & Donafenib) are used to build a pharmacophore model with ‘PharmaGist webserver’ which generated a 5-point hypothesis. The best model with score of 27.780, was used to screen the Zinc database of ZINCPharmer web server to obtain similar pharmacophore hits. By applying filters like Lipinski rule, RMSD criteria in ZINCPharmer top ten hits were identified. Subsequently, molecular docking was performed on wild (1UWH) and mutated (3IDP) B-Raf kinase protein targets by using GLIDE 5.6 (Schrödinger), to prioritize top lead molecules. Further these molecules are subjected to ADME Properties Prediction by Qik Prop module. Among ten, nine molecules have glide scores in the range nearer to the standard molecule i.e., Sorafenib. Finally, we conclude that ZINC02853810 may act as a powerful inhibitor against both wild and mutant type B-Raf kinase as it has highest glide scores than the Standard. 
 GRAPHICAL ABSTRACT