Computational Design Synthesis Characterization and Pharmacological Evaluation of Some Piperidine Derivatives

Abstract

The Aurora kinase family is a collection of highly related serine/threonine kinases that functions as a key regulator of mitosis. In mammalian cells, Aurora has evolved into three related kinases known as Aurora-A, Aurora-B, and Aurora-C. These kinases are over expressed in a number of human cancers, and transfection studies have established Aurora-A as a bone fide oncogene. Because Aurora over expression is associated with malignancy, these kinases have been targeted for cancer therapy. In the present study, it was decided to design some inhibitory lead compounds of Aurora kinase A as using computational tools like Catalyst and GLIDE. Eighty two Aurora A kinase inhibitors from Medicinal Chemistry Journals were selected for modeling studies based on chemical and biological diversity. The selected molecules were then divided into 21 training set molecules and 61 test set molecules. Using the training set molecules pharmacophore models were generated in Hypogen. The most active molecule in the training set fits very well with the top scoring pharmacophore hypothesis. The model developed was shown to be a good model with 0.65 as Goodness of Hit score (GH) and an enrichment factor of 1.154. GLIDE was the docking program used for the structure based drug design. To conclude the anticancer leads obtained in this study can be refined further to get a potent anticancer molecules. Drugs targeting multiple kinases have proven to be effective against treatment of various diseases. The activities of serine/threonine protein phosphatases needs further study, but it is clear that these enzymes are potential targets for novel therapeutics with applications in many diseases, including cancer, inflammatory diseases and neuro degeneration. Computational techniques have provided starting points for designing multiple inhibitors against individual targets using crystal structural information of kinases and pharmacophore of kinase inhibitors. So these techniques can be explored further to design new drug candidates for various diseases. newline