Design and identification of novel candidates against the tyrosine kinase domain of alk by comprehensive in silico approaches

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, 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 and Lorlatinib, which is a second-generation and third generation ALK inhibitors, respectively. Given these points, this study focused on two distinct paths to discover and develop novel compounds that could target tyrosine kinase domain of the ALK. Firstly, 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, and MM/PBSA binding free energy calculation. As a second approach, we virtually screened a large natural product database to a novel drug candidate for possibly inhibiting ALK TK and investigated their binding properties by similar ways utilised in the first approach. Considering the obtained results, we developed three promising candidates, compounds 208, 209 and CNP106316.1 with -9.08, -9.80, and -11.6 kcal/mol and binding energies respectively, which demonstrated improved binding profiles over their respective MD simulations, 300ns for carbolines, 500ns for the NP.