The influence of electron donor and electron acceptor groups on the electronic structure of the anti‐inflammatory tripeptide Cys‐Asn‐Ser

It has been discussed in the literature that electron delocalization along the peptide backbone and side chain modulates the physical and chemical features of peptides and proteins. The structure and properties of peptides are determined by their charge‐density distribution, such that the modification of its side chain plays an important role on its electronic structure and physicochemical properties. Research on Entamoeba histolytica soluble factors led to the identification of the pentapeptide Met‐Gln‐Cys‐Asn‐Ser, with anti‐inflammatory in vivo and in vitro effects. A synthetic pentapeptide, Met‐Pro‐Cys‐Asn‐Ser, maintained the same anti‐inflammatory actions in experimental assays. A previous theoretical study allowed proposing the Cys‐Asn‐Ser tripeptide (CNS tripeptide) as the pharmacophore group of both molecules. This theoretical hypothesis was recently confirmed experimentally. The objective of this work was to study the influence of the electron donor and electron withdrawing substituent groups on the electronic structure and physicochemical properties of the CNS tripeptide derivatives through a theoretical study at the density functional theory level of theory. Our results in deprotonation energies showed that the relative acidity of hydrogen atom (H2) of the serine‐amide group increases with the electron withdrawing groups. This result was confirmed by means of a study of bond order. The proton affinities illustrated that the electron donor groups favored the basicity of the amino group of the cysteine amino acid. Atomic charges, Frontier molecular orbitals (HOMO–LUMO), and electrostatic potential isosurface and its geometric parameters permitted to analyze the effect that provoked the electron donor and electron attractor groups on its electronic structure and physicochemical features and to identify some reactive sites that could be associated with the anti‐inflammatory activity of tripeptide CNS derivatives. © 2010 Wiley Periodicals, Inc. Int J Quantum Chem 110:2398–2410, 2010