In Silico Bioisosteric Replacements of hnRNP K Ligands as Anticancer Lead Compounds

Abstract

Heterogeneous ribonucleoprotein K (hnRNP K) is a constitutive protein found in nucleus, cytoplasm and mitochondria of cells and interacts with diverse molecules involved in gene expression and signal transduction. Its over expression is associated with the development of prostate, breast and colorectal cancer types. The binding to nucleotides is the main interaction that triggers biological activity and is mediated by its three K homology (KH) domains. Trying to optimize a benzimidazole and a phenylbenzamide derivatives, already reported as hnRNP K ligands, and generate novel ligand candidates with potential anticancer activity, bioisosteric replacements were suggested in the molecular groups able to perform polar interactions with R40 and R59, the main residues of KH3 domain responsible for nucleotide recognition. The top-ranked fragments from BROOD database regarding interaction with the protein, and also steric and electrostatic similarity with query fragments, were selected as potential bioisosters. The novel fragments when inserted in the benzimidazole and phenyilbenzamide derivatives could interact with R40 or R59 by hydrogen bond or ionic interaction. Some of the selected fragments show toxicophoric groups able to induce hepatotoxicity, carcinogenicity and chromosome damage. In this way, the bioisosters without classical toxicophoric groups should be prioritized for synthesis of novel lead compounds, generating diversity in the continuous search of effective and safer anticancer drugs.