FINDING NEW INHIBITORS FOR EML4-ALK FUSION PROTEIN: A COMPUTATIONAL APPROACH

The fusion between echinoderm microtubule-associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK) has recently been identified in a subset of non-small cell lung cancers (NSCLC). PF-02341066 (crizotinib) is an orally bioavailable ALK inhibitor currently under clinical development. PF-02341066 in EML4-ALK NSCLC was designed for patients not eligible for the phase III trial or patients randomized to chemotherapy who subsequently developed progressive disease. PF-02341066 is a dual inhibitor of mesenchymal epithelial transition growth factor (c-met) and anaplastic lymphoma kinase translocation gene and caused tumour shrinkage in 52% of patients in a phase I study. However, some studies also show denovo mutations within the kinase domain of EML4-ALK that confers resistance to multiple ALK inhibitors. Hence development of new inhibitors with better binding affinities towards the EML4-ALK is the need of the hour for subsequent clinical validation. Computational (virtual) screening of drug-like compounds against the protein targets like EML4-ALK, might help to identify specific lead inhibitors more efficiently. The Protein- Ligand interaction plays a significant role in structure based drug designing. In the current study, we have considered EML4-ALK, a fusion protein involved in NSCLCs as a receptor and NCI subset Ligands as drugs. The receptor was docked to the NCI database of drugs and a docking score was calculated using GLIDE docking software. Based on the docking score, we choose the best drugs and analyzed its ADME properties using Qikprop tool. The results of this analysis show some novel compounds that can be further evaluated as EML4-ALK inhibitors in experimental NSCLC cell lines. The study further supports the application of computer-aided techniques to the discovery of novel and specific drug for EML4-ALK fusion protein.