Novel Human Kynurenine Aminotransferase Type II (KAT II) Inhibitors:A Computational Approach toward Schizophrenia Treatment

Introduction: Inhibitors targeting human kynurenine aminotransferase 2 (KATII) have potential therapeutic applications for addressing cognitive dysfunctions associated with schizophrenia and bipolar disorder. This study aims to discover and evaluate novel inhibitors of the KATII enzyme using drug discovery methods, to identify compounds with therapeutic potential in schizophrenia. background: Inhibitors targeting human kynurenine aminotransferase 2 (KATII) have potential therapeutic applications for addressing cognitive dysfunctions associated with schizophrenia and bipolar disorder. Methods: In this study, we present various chemical series of KATII inhibitors discovered through high-throughput screening of a diverse compound library. Computational approaches included virtual screening, binding free-energy calculations, and molecular dynamics. objective: The aim of this study is to discover and evaluate novel inhibitors of the KATII enzyme using drug discovery methods, in order to identify compounds with therapeutic potential in schizophrenia. Results: We utilized thirteen million compounds that were found in the Mcule library. We also used previously known KATII inhibitor compounds as positive controls, such as N-acetylcysteine, and PF-04859989. Based on the simulation analysis and the binding energy of the ligands, three ligands ZINC02761616 (-93.906 kJ mol-1), ZINC04577733 (-114.107 kJ mol-1), and ZINC75093839 (- 103.388 kJ mol-1), were proposed as the best inhibitors for this in vitro study. Also, the binding energy of compounds N-acetylcysteine and PF-04859989 was 28.984 kJ mol-1 and -14.124 kJ mol-1, respectively. Discussion: The novel compounds demonstrated stronger binding affinities than existing KATII inhibitors, indicating potential for improved schizophrenia treatment. However, computational predictions require experimental validation to assess solubility and off-target effects. Conclusion: These compounds may offer enhanced potency, but in vitro and in vivo studies are essential to confirm their efficacy and safety.