Structure-Based Drug Design of Kinase Inhibitors for Targeted Cancer Therapy

Abstract

The recent increased focus on high precision of cancer treatment has fueled the advancement of molecularly targeted inhibitors especially the kinase inhibitors, which interfere with the signaling pathway involved in oncogenesis in a highly specific manner. This paper uses a structure-based drug design (SBDD) to determine and develop novel kinase inhibitors based on the in silico approach used comprehensively. All 100 kinase-ligand complexes were docked, profiled, and screened on binding interactions and pharmacokinetics. Besides, two structure-based designed lead compounds revealed high binding affinities to several relevant cancer-related targets like BCR-ABL, EGFR, and VEGFR, and scored low with an energy value as low as -10.2 Kcal/mol compared to current inhibitors. Interaction-related studies revealed the possibilities of stable ligand binding through hydrogen bridges and hydrophobic contacts, whereas screening with ADMET properties revealed good drug-like properties and oral absorption. The Lead Compound 1 turned out to be the most encouraging one, being highly specific, significantly non-toxic, and excellently pharmacokinetically. The results support the usefulness of SBDD to discover effective and selective kinase-targeting anticancer drugs as a basis of continuing the preclinical verification and development of the project.