Stable Complexes of LYN Kinase and Druglike Small Molecules

Abstract

Glioblastoma multiforme (GBM) is a very aggressive brain cancer in humans. Even with improvements in surgical, radiation, and chemotherapy treatments, current prognosis is bleak, with only a 14-month median survival time. LYN, an important kinase involved in cell regulation, is often overexpressed in GBM. This work addresses computational design of druglike small molecules that could potentially inhibit LYN and thus hinder GBM progression. New putative LYN inhibitors were obtained by atomic substitutions and structural alterations of bafetinib, a small molecule previously found to bind LYN. Druglike properties and toxicities of the designed molecules were evaluated using the Osiris Property Explorer program. Molecules with no implied toxicities and most favorable druglike properties were used for docking studies in the ArgusLab program. Designed molecules that made the most stable docking configurations with LYN, but no stable configurations with other kinases, were identified as LYN-specific. Binding energies of the stable complexes formed by these molecules and LYN were calculated. Possible utilization of the designed molecules in drug research against GBM is discussed.