Title:In Silico Bioisosteric Replacements of hnRNP K Ligands as Anticancer Lead Compounds
VOLUME: 4 ISSUE: 1
Author(s):Vinicius B. Da Silva, Andreia M. Leopoldino and Carlos H.T.P. Da Silva
Affiliation:Departamento de Biomedicina e Farmacia, Pontifícia Universidade Católica de Goiás, Rua 232, n° 128, Setor Leste Universitário, 74605-140, Goiânia – Brasil.
Keywords:Hydrogen bonds, novel lead compounds, proteins, steric and electrostatic similarity.
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.
