Prediction of alternate drugs for crizotinib resistant mutated-alk inhibitors in lung cancer treatment: An In silico approach

Resistance to the drug crizotinib due to the mutation of its target protein, Anaplastic Lymphoma Kinase (ALK) is a significant drawback for treatment of patients suffering from lung cancer. The aim of the study was to identify a drug compound which is structurally, physiologically and functionally similar to crizotinib which will act as a replacement in lung cancer therapy. Structural alignment was performed to gain greater perspective wherein the Z-scores and RMSD values reveal drug molecules of significant similarity to crizotinib. Pharmacophore analysis was performed using an online webserver called Pharma Gist to compare the pharmacophores of data set drugs to the pharmacophore of crizotinib. The structural and physiological similarity were investigated using Chem Mine and to generate similarity indices between crizotinib and the test molecules. Binding energy studies were performed using Autodock 4.0 to filter out drug molecules which are chosen such that the binding energy corresponding to the mutant ALK is less negative than that of native ALK. The number of clusters forms and the number of hydrogen bonds were also kept in mind while choosing the molecules. The required molecule was identified after strict analysis and filtering procedures, providing a replacement drug molecule for improved therapeutic use.