6-hydroxy-3-succinoylsemialdehyde-pyridine as a potential inhibitor of schizophrenia-associated enzyme

Abstract Schizophrenia’s cognitive deficits limit quality of life. Current drugs are ineffective. This study investigates 6-hydroxy-3-succinoylsemialdehyde-pyridine (6H3SAP), a nicotine derivative, as a potential inhibitor of KATII, an enzyme in the kynurenine pathway linked to cognitive dysfunction. Molecular docking was employed to assess the binding affinity of 6H3SAP to the KATII enzyme. The results indicated that 6H3SAP interacted with the KATII active site, demonstrating a binding affinity comparable to nicotine (previously suggested as a potential KATII blocker) but lower than NS1502, a well-established KATII inhibitor. Subsequent molecular dynamics simulations provided further insights into the interaction details between 6H3SAP and KATII. These simulations revealed the formation of stable interactions between 6H3SAP and key amino acid residues within the KATII binding pocket. Though promising, further research is needed to assess 6H3SAP’s efficacy and safety. Surprisingly, the molecular dynamics data also proposed that the nicotine-KATII tie is weak.