Molecular dynamics simulation, binding free energy calculation and molecular docking of human D-amino acid oxidase (DAAO) with its inhibitors

Abstract

Schizophrenia is a mental illness; most affected people live in developing countries, and neither appropriate treatment nor commercial drugs are currently available. One possibility is to inhibit human-d-amino acid oxidase (h-DAAO). In this study, molecular dynamic simulations of the monomer, dimer and tetramer forms of h-DAAO complexed with the inhibitor 3-hydroxyquinolin-2(1H)-one(2) were performed. Seven residues, Leu51, Gln53, Leu215, Tyr228, Ile230, Arg283 and Gly313, were identified as essential for interacting with the inhibitor. Molecular docking of h-DAAO with pyrrole, quinoline and kojic acid derivatives, representing 69 known or potential h-DAAO inhibitors, was also performed. The results indicated that the activity of the inhibitor can be improved by modifying the compounds to have a substituent group capable of interacting with the side chain of Tyr228. Van der Waals interactions of the inhibitor with the hydrophobic pocket of h-DAAO and electrostatic interactions or H-bonds with Arg283 and Gly313 were important elements in determining the efficiency of the inhibitor. These results provide information on the interaction between h-DAAO and its inhibitors at the molecular level and can aid in the design of novel inhibitors against h-DAAO for new drug development in the treatment of schizophrenia.

Keywords::

• schizophrenia
• h-DAAO
• molecular dynamics simulation
• molecular docking

Acknowledgements

This work was supported by a Ratchadaphiseksomphot Endowment Fund Postdoctoral Fellowship from Chulalongkorn University. The authors thank the Computational Chemistry Unit Cell, Faculty of Science, Chulalongkorn University, for providing research facilities, software packages and computational sources. K.W. additionally thanks the Institute of Pharmacy, Martin-Luther University Halle-Wittenberg, Halle (Saale), Germany, for providing the MOE software programs.