THEORETICAL INVESTIGATION OF ELECTRON TRANSFER PROCESS IN D-AMINO ACID OXIDASE WITH ITS INHIBITORS

Abstract

The photoinduced electron transfer (PET) rates between Iso and nearby amino acid residues of D-amino acid oxidase (DAAO) were studied using Kakitani-Mataka ET theory and DAAO conformations from molecular dynamics (MD) simulation. These PET rates of DAAO were inspired to a novel way for discovery new DAAO inhibitors by inhibiting ET process. The first part of this thesis, the interaction and dynamics properties of DAAO from pig kidney for four systems i.e. DAAO monomer, DAAO dimer, DAAO complexed with benzoate (DAOB) monomer, and DAOB dimer were studied by MD simulations. DAAO and DAOB MD simulation results revealed the different conformations between monomer and dimer, as well as the non-equivalent conformations in dimer. The results of PET analysis of DAAO showed that the three fastest ET rates are from Tyr224, Tyr228, and Tyr314 to Iso* of DAAO. The benzoate in DAOB, as a competitive inhibitor, is the best electron donor to Iso* compare to other amino acids which is agreed with the experimental fluorescence lifetime quenching. The second part of this thesis, DAAO from human was studied to find potential DAAO inhibitors for schizophrenia treatment using virtual screening technique. Four million compounds on Namiki database were screened using pharmacophore model and molecular docking. The 22 hit compounds will be tested biological activity.