Docking-based virtual screening of pyrrole containing imatinib structure analogs

Abstract

Tyrosine kinase inhibitors became a common treatment option for chronic myelogenous leukemia (CML). Still secondary resistance of patients connected with disease progression remains a major challenge. More effective kinase inhibitors are of great need. In this study, design and molecular docking of combinatory library of de novo imatinib-like structures was performed using Autodock Vina. The main design approach was to replace a benzene linker in the structure of imatinib with a pyrrole ring. Crystal structures of CML-related C-ABL, Human ABL and T315I mutant ABL were used as receptors. Ligands were prepared in MGL Tools. Chimera 1.10 was used for receptor preparation, binding site parametrization and visualization of results. Vina’s exhaustiveness of search was set to 24. All docked structures were filtered based on the known inhibitors results. Two structures showed the promising predicted binding affinities (Autodock Vina’s score -13.6 and -13.1 respectively) comparable with those of approved kinase inhibitors imatinib and nilotinib.