Discovery of a Novel Class of D-Amino Acid Oxidase Inhibitors Usingthe Schro?dinger Computational Platform br

D-Serine is a coagonist of theN-methylD-aspartate(NMDA) receptor, a key excitatory neurotransmitter receptor. Inthe brain,D-serine is synthesized from itsL-isomer by serineracemase and is metabolized by the D-amino acid oxidase (DAO,DAAO). Many studies have linked decreasedD-serine concen-tration and/or increased DAO expression and enzyme activity toNMDA dysfunction and schizophrenia. Thus, it is feasible toemploy DAO inhibitors for the treatment of schizophrenia andother indications. Powered by the Schro??dinger computationalmodeling platform, we initiated a research program to identifynovel DAO inhibitors with the best-in-class properties. Theprogram execution leveraged an hDAO FEP+ model to prospectively predict compound potency. A new class of DAO inhibitorswith desirable properties has been discovered from this endeavor. Our modeling technology on this program has not only enhancedthe efficiency of structure-activity relationship development but also helped to identify a previously unexplored subpocket forfurther optimization.