Discovery of a Novel Class of d‑Amino Acid Oxidase Inhibitors Using the Schrödinger Computational Platform

d-Serine is a coagonist of the N-methyl d-aspartate (NMDA) receptor, a key excitatory neurotransmitter
receptor. In the brain, d-serine is synthesized from its l-isomer by serine racemase and is metabolized by the D-amino
acid oxidase (DAO, DAAO). Many studies have linked decreased d-serine concentration and/or increased DAO expression and enzyme
activity to NMDA dysfunction and schizophrenia. Thus, it is feasible
to employ DAO inhibitors for the treatment of schizophrenia and other
indications. Powered by the Schrödinger computational modeling
platform, we initiated a research program to identify novel DAO inhibitors
with the best-in-class properties. The program execution leveraged
an hDAO FEP+ model to prospectively predict compound potency. A new
class of DAO inhibitors with desirable properties has been discovered
from this endeavor. Our modeling technology on this program has not
only enhanced the efficiency of structure–activity relationship
development but also helped to identify a previously unexplored subpocket
for further optimization.