Mitoxantrone and abacavir: An ALK protein-targeted in silico proposal for the treatment of non-small cell lung cancer

Abstract

Non-small cell lung cancer (NSCLC) is a type of lung cancer associated with translocation of the EML4 and ALK genes on the short arm of chromosome 2. This leads to the development of an aberrant protein kinase with a deregulated catalytic domain, the cdALK+. Currently, different ALK inhibitors (iALKs) have been proposed to treat ALK+ NSCLC patients. However, the recent resistance to iALKs stimulates the exploration of new iALKs for NSCLC. Here, we describe an in silico approach to finding FDA-approved drugs that can be used by pharmacological repositioning as iALK. We used homology modelling to obtain a structural model of cdALK+ protein and then performed molecular docking and molecular dynamics of the complex cdALK+-iALKs to generate the pharmacophore model. The pharmacophore was used to identify potential iALKs from FDA-approved drugs library by ligand-based virtual screening. Four pharmacophores with different atomistic characteristics were generated, resulting in six drugs that satisfied the proposed atomistic positions and coupled at the ATP-binding site. Mitoxantrone, riboflavin and abacavir exhibit the best interaction energies with 228.29, 165.40 and 133.48 KJoul/mol respectively. In addition, the special literature proposed these drugs for other types of diseases due to pharmacological repositioning. This study proposes FDA-approved drugs with ALK inhibitory characteristics. Moreover, we identified pharmacophores sites that can be tested with other pharmacological libraries.

Kinase Inhibitors and Kinase-Targeted Cancer Therapies: Recent Advances and Future Perspectives

“…Machine learning methods show promise in the repurposing of existing kinase inhibitors or compounds already in clinical use for cancer treatment and other diseases. Enrique et al used computational techniques to identify mitoxantrone and abacavir as potential drugs for ALK-positive NSCLC and validated this combination in in vitro experiments [198]. Muthuraj et al employed the t-SNE algorithm and ECFP4 fingerprints to screen derivatives of palbociclib and ribociclib, identifying DE50607359 as a promising WEE1 inhibitor, pending experimental validation [199].…”