Molecular Dynamics Simulation of Kynurenine Aminotransferase Type II with Nicotine as a Ligand: A Possible Biochemical Role of Nicotine in Schizophrenia

Homodimeric KATII is an enzyme involved in l-kynurenine transamination to kynurenic acid. The increase in kynurenic acid concentration is predominant in schizophrenia and other disorders. Currently, the search for new KATII inhibitors continues to be a challenge. The aim of this work was to analyze the possible role of nicotine in KATII inhibition and compare it with the reversible inhibitor NS1502. We have used computational methods of quantum mechanics, docking, molecular dynamics, and binding energy (molecular mechanics/Poisson-Boltzmann surface area). The results of chemical reactivity showed that the nucleophilic and electrophilic attacks would be more significant in nicotine than in NS1502. The molecular dynamics simulations provided a molecular understanding of the binding interaction of nicotine and NS1502 with KATII. The nicotine binding energy was similar to that of the NS1502 compound; both were placed in the same pocket. Furthermore, the energy distribution analysis of ligands to cofactor lysine pyridoxal-5′-phosphate presented similar values in both cases; consequently, the electrostatic potential of the active site was positive, which leads us to believe that nicotine behaves as the reversible inhibitor NS1502 and could play a neuroprotective role in schizophrenia.