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The Kynurenine aminotransferase II (KATII) enzyme has an essential role in L-kynurenine transmission to kynurenic acid (KYNA). High concentration of kynurenic acid associates with schizophrenia and some neurocognitive disorders. Decreasing KYNA production via inhibiting KATII would be an effective method for treating and understanding the related central nervous system (CNS) diseases. This study aimed to discover a potent inhibitor against human KATII (hKATII) in comparison with PF-04859989. We utilized the computational methods of molecular dynamics, virtual screening, docking, and binding free-energy calculations. Initially, the 58722 compounds from three drug libraries, including IBS library, DrugBank library, and Analyticon library, were obtained. At the next stage, these sets of compounds were screened by AutoDock Vina software, and a potent inhibitor (ZINC35466084) was selected. Following the screening, molecular dynamics simulations for both ZINC35466084 and PF-04859989 were performed by GROMACS software. MM-PBSA analysis showed that the amount of binding free energy for ZINC35466084 (–61.26 KJ mol −1 ) is more potent than PF-04859989 (–43.14 KJ mol −1 ). Furthermore, the ADME analysis results revealed that the pharmacokinetic parameters of ZINC35466084 are acceptable for human use. Eventually, our data demonstrated that ZINC35466084 is suitable for hKATII inhibition, and it is an appropriate candidate for further studies in the laboratory. Communicated by Ramaswamy H. Sarma

journal of biomolecular structure and dynamics

Designing a natural inhibitor against human kynurenine aminotransferase type II and a comparison with PF-04859989: a computational effort against schizophrenia