CONFORMATIONAL BEHAVIOR OF HYDRAZONE DERIVED FROM PYRIDOXAL 5’-PHOSPHATE AND ISONIAZID

The hydrazones derived from pyridoxal or pyridoxal 5’-phosphate and heterocyclic hydrazides are of interest due to their potential biological activity and metal sensing properties. These characteristics of hydrazones could be dependent on the conformation equilibria of molecule since the most stable conformer could differ from the one with the highest affinity towards biomolecule or metal ion. In the present contribution, deprotonated hydrazone formed by pyridoxal 5’-phosphate and isoniazid (PLP-INH3-) was studied by means of quantum chemistry. Three rotations leading to eight conformers are possible for this hydrazone; however, four of those species obtained by rotation of pyridine ring of isoniazid residue are degenerated. The geometry of different non-degenerated rotation conformers of the hydrazine (differing by the mutual arrangement of carbonyl group of the isoniazid residue and oxygen in 3’-site of PLP moiety) was optimized using density functional theory (B3LYP/6-311++G(d,p)). Activation barriers were evaluated. Changes in energy and geometry of conformers as well as transition states are discussed. Quantitative QTAIM (Quantum Theory of Atoms in Molecules) analysis was performed in order to check the intermolecular hydrogen bonding existence. The species capable of forming the complex with the metal ions differs from the most stable (according to the total energy values) conformer. The preliminary prediction of biological activity of PLP-INH3- hydrazone and the docking for the hydrazone and G-protein-coupled receptor kinase were performed and the preferable conformation for ligand binding to the kinase active site was found.