Computational design of targeted inhibitors of polo-like kinase 1 (plk1).

Computational design of small molecule putative inhibitors of Polo-like kinase 1 (Plk1) is presented. Plk1, which regulates the cell cycle, is often over expressed in cancers. Down regulation of Plk1 has been shown to inhibit tumor progression. Most kinase inhibitors interact with the ATP binding site on Plk1, which is highly conserved. This makes the development of Plk1-specific inhibitors challenging, since different kinases have similar ATP sites. However, Plk1 also contains a unique region called the polo-box domain (PBD), which is absent from other kinases. In this study, the PBD site was used as a target for designed Plk1 putative inhibitors. Common structural features of several experimentally known Plk1 ligands were first identified. The findings were used to design small molecules that specifically bonded Plk1. Drug likeness and possible toxicities of the molecules were investigated. Molecules with no implied toxicities and optimal drug likeness values were used for docking studies. Several molecules were identified that made stable complexes only with Plk1 and LYN kinases, but not with other kinases. One molecule was found to bind exclusively the PBD site of Plk1. Possible utilization of the designed molecules in drugs against cancers with over expressed Plk1 is discussed.

Inhibition of Antiapoptotic BCL-XL, BCL-2, and MCL-1 Proteins by Small Molecule Mimetics.

Informatics and computational design methods were used to create new molecules that could potentially bind antiapoptotic proteins, thus promoting death of cancer cells. Apoptosis is a cellular process that leads to the death of damaged cells. Its malfunction can cause cancer and poor response to conventional chemotherapy. After being activated by cellular stress signals, proapoptotic proteins bind antiapoptotic proteins, thus allowing apoptosis to go forward. An excess of antiapoptotic proteins can prevent apoptosis. Designed molecules that mimic the roles of proapoptotic proteins can promote the death of cancer cells. The goal of our study was to create new putative mimetics that could simultaneously bind several antiapoptotic proteins. Five new small molecules were designed that formed stable complexes with BCL-2, BCL-XL, and MCL-1 antiapoptotic proteins. These results are novel because, to our knowledge, there are not many, if any, small molecules known to bind all three proteins. Drug-likeness studies performed on the designed molecules, as well as previous experimental and preclinical studies on similar agents, strongly suggest that the designed molecules may indeed be promising drug candidates. All five molecules showed "drug-like" properties and had overall drug-likeness scores between 81% and 96%. A single drug based on these mimetics should cost less and cause fewer side effects than a combination of drugs each aimed at a single protein. Computer-based molecular design promises to accelerate drug research by predicting potential effectiveness of designed molecules prior to laborious experiments and costly preclinical trials.