In Silico Design of Phenylbenzamide Derivatives Coupled to Pyrimidines as Novel hnRNP K Ligands Against Cancer
Matheus G. de Oliveira,
Andreza S. Figueredo,
Gilberto L.B. de Aquino,
Andreia M. Leopoldino,
Vinicius B. da Silva,
Carlton A. Taft,
Carlos H.T. de Paula da Silva.
Cancer disease is characterized by genomic abnormalities and gene expression aberrations that leads to
misregulated activity of apoptosis, angiogenesis and cell proliferation. Heterogeneous ribonucleoprotein K (hnRNP K) is
a constitutive protein found in nucleus, cytoplasm and mitochondria of cells and interacts with molecules involved in gene
expression and signal transduction pathways. It is believed that the over expression of hnRNP K leads to 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 phenylbenzamide derivative, already reported as an
hnRNP K ligand, and design novel ligand candidates with anticancer activity, synthetically viable phenylbenzamide derivatives
coupled to pyrimidine nucleosides were evaluated in silico by docking simulations with KH3 domain of hnRNP
K. The cytosine nucleoside and phenylbenzamide moieties could be able of simulating the polar interactions performed by
natural celular nucleotide ligands with ARG40 and ARG59, the main residues of KH3 domain responsible for nucleotide
recognition. Ligand-based in silico biological activity spectrum evaluation also revealed that phenylbenzamide coupled to
pyrimidine nucleosides are potential anticancer candidates.
Keywords: Biological activity spectrum, cancer, hnRNP K, phenylbenzamide derivatives, pyrimidines.
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