Anticancer Lead Compounds that Prevent DNA Binding to hnRNP K

hnRNP K is an important constitutive protein in which is found in the nucleus, cytoplasm, and mitochondria of cells. As such, this protein interacts in turn with various molecules, which are directly involved in gene expression as well as signal transduction. However, it is well-known that its aberrant expression is related to the development of most commonly diagnosed cancers, including prostate, lung, breast, and colorectal. Hence, the binding to nucleotides is the main molecular event responsible for triggers the biological activity of hnRNP K and in which is mediated by its K homology (KH) domains. Using the structure of KH3 domain, virtual screening simulations were then performed by docking using GOLD software to select small molecules that could compete with nucleotides by the binding site of the domain, intending to block the protein activity and discover new lead compounds against cancer. In vitro assays revealed the discovery of a benzimidazole and a phenylbenzamide derivative able to prevent DNA binding to hnRNP K. The molecular interaction fields computed for hydrophobic and polar interactions for KH3 structure and molecular dynamics simulations with docked compounds revealed energetically viable binding modes for these derivatives, where arginine protein residues should play a central role in molecular recognition. The design of benzimidazole and phenylbenzamide derivatives enriches the knowledge of lead compounds in the search for a novel class of anticancer drugs able to down-regulate hnRNP K.