Resumen de Design and discovery of new potential dual kinase back-pocket binders by fragmentation and virtual screening of natural products
The discovery of new and better drugs is a costly and slow process in which the identification of optimal preclinical candidates is often a difficult task. To overcome this drawback, fragment based drug design (FBDD), virtual screening (VS) and the use of natural products (NP) have become powerful strategies aimed at exploring the chemical space in silica more broadly and improving the likelihood of finding innovative lead molecules more quickly and cost-effectively. On the other hand, we currently know that Cycline-Dependent Kinase 2 (CDK2) and Vascular-Endothelial Growth Factor Receptor 2 (VEGFR2) are human enzymes with a key role in signaling pathways responsible for cell proliferation, angiogenesis and metastasis, widely recognized as traits associated with cancer. While there is no officially approved antineoplastic drug to date that targets these enzymes as its primary targets, both may adopt an "inactive" conformation in which a posterior allosteric pocket at the accessible active site has been reported as a highly strategic interaction target to achieve greater selectivity. As a result of our research, we demonstrated that a combined protocol of VS and natural product derived fragments (NPDF) was successful in designing a set of virtual dual CDK2/VEGFR2 inhibitor candidates. These compounds possess potentially innovative, diverse and potent chemical frameworks that can be taken to eventual rounds of synthesis, biochemical assays and structural analysis for optimization. The results of this thesis project are intended to contribute both to the generation of new computational methods and to the identification of bioactive compounds against cancer and many other diseases still rampant all around the world
