Toward the Design of New α‐Carboline Derivatives Against Anaplastic Lymphoma Kinase (ALK): A Comprehensive In Silico Approach

Abstract After the first description of anaplastic lymphoma kinase (ALK) in an anaplastic large cell lymphoma cell line as a nucleophosmin (NPM) fusion partner, ALK and its various fusion partners have been implicated in numerous cancers such as non‐small cell lung cancer (NSCLC), anaplastic large cell lymphoma (ALCL), neuroblastoma, and rhabdomyosarcoma. In the last decade, several compounds targeting ALK have been developed and approved by the Food and Drug Administration (FDA). Despite the advances of generations of ALK inhibitors, a recent study highlighted that around half of the ALK‐positive NSCLC patients will go through disease progression in response to first‐line alectinib, which is a second‐generation ALK inhibitor. In this study, we aimed to propose a novel α‐carboline compound targeting the ALK tyrosine kinase domain to be used against various types of cancer in which ALK fusion proteins may be involved. In this regard, we designed more than 200 α‐carboline derivatives and investigated their binding properties against ALK tyrosine kinase by using in silico protocols consisting of molecular docking studies, molecular dynamics simulations, MM/PBSA binding free energy calculation, and essential dynamics analysis. Considering the obtained results, we developed two promising candidates, compounds 208 & 209 with −9.05 and −9.80 binding energies, respectively, which demonstrated improved binding profiles over the course of a 300 ns simulation.