EGFR1, VEGFR2, Bcr-Abl and Src kinases are key drug targets in non-small cell lung cancer (NSCLC), bladder cancer, pancreatic cancer, CML, ALL, colorectal cancer, etc. The available drugs targeting these kinases have limited therapeutic efficacy due to novel mutations resulting in drug resistance and toxicity, as they target ATP binding site. Allosteric drugs have shown promising results in overcoming drug resistance, but the discovery of allosteric drugs is challenging. The allosteric binding pockets are difficult to predict, as they are generally associated with high energy conformations and regulate protein function in yet unknown mechanisms. In addition, the discovery of drugs using conventional methods takes long time and goes through several challenges, putting the lives of many cancer patients at risk. Therefore, the aim of the present work was to apply the most successful, drug repurposing approach in combination with computational methods to identify kinase inhibitors targeting novel allosteric sites on protein structure and assess their potential multi-kinase binding affinity. Multiple crystal structures belonging to EGFR1, VEGFR2, Bcr-Abl and Src tyrosine kinases were selected, including mutated, inhibitor bound and allosteric conformations to identify potential leads, close to physiological conditions. Interestingly the potential inhibitors identified were peptides. The drugs identified in this study could be used in therapy as a single multi-kinase inhibitor or in a combination of single kinase inhibitors after experimental validation. In addition, we have also identified new hot spots that are likely to be druggable allosteric sites for drug discovery of kinase-specific drugs in the future.Communicated by Ramaswamy H. Sarma.
Keywords: Tyrosine kinases; allosteric inhibitors; docking; drug repurposing; interaction fingerprints; ligands; multi-kinase; signaling pathways.