Small Druglike Molecules with Specific Binding to Plk1 Or LYN Kinases

Abstract

The research addresses computational design of small druglike molecules for possible anticancer applications. Polo-like kinase 1 (Plk1) is a main regulator of mitosis. Its inhibition can lead to apoptosis of cancer cells. Most kinases interact with inhibitors via their highly conserved ATP sites. This makes the design of Plk1-specific inhibitors challenging. However, Plk1 also has the polo-box domain (PBD) that is absent from other kinases. Previously, we designed several molecules that interacted with the PBD of Plk1 and with only one other kinase, LYN. The LYN kinase regulates hematopoietic cells from which cellular blood components are derived. Yet, LYN's greatly elevated activity in glioblastoma tumors suggests that it promotes the malignancy in these cells. In light of their respective cellular roles, it is important to design inhibitors that are either Plk1- or LYN-specific. This is not trivial because of their very similar binding sites. Physicochemical differences between the sites were analyzed in the DeepView program. Relevant atomic distances within the PBD of Plk1 were found greater than those within LYN. Thus, a larger molecule could potentially fit into the PBD and would be excluded from the LYN's smaller and less flexible site. Previously designed molecules that bonded both Plk1 and LYN were used as templates to design more specific inhibitors. Designed molecules with no indicated toxicities and optimal values of other drug-related properties were used for docking in ArgusLab. Molecules that made stable complexes specifically with either Plk1 or LYN, but with no other kinases, were identified. Drugs based on these molecules could be useful against tumors with overexpressed Plk1 or LYN. Such drugs could selectively bind one of the kinases and lead to fewer side effects than a less selective drug.