Discovery of NMDA Glycine Site Inhibitors from the Chemical Universe Database GDB

Drug development faces the ever-increasing challenge of discovering new bioactive small molecules that have not already been investigated in the more than 150-year history of medicinal chemistry. [1] This problem is particularly critical for drug targets that require very small organic ligands, for which the range of potential structures is limited. One possible way to overcome this difficulty would be to search through the entire chemical space of these small molecules using virtual screening tools and to identify promising ligands for synthesis and testing. Herein we report the first example of such an approach for ligands of the N-methyl-d-aspartic acid (NMDA) receptor glycine site. This receptor is an important drug target implicated in synaptic plasticity, neuronal development, learning, and memory. Inhibiting the NMDA receptor may help prevent neuronal cell death caused by glutamate excitotoxicity in acute and chronic neurodegenerative disorders such as stroke, epilepsy, Huntington’s, and Alzheimer’s disease. [2] Starting with our recently reported chemical universe database (GDB) that lists all compounds of C, N, O, and F up to 11 atoms obeying simple stability and synthetic feasibility rules, [3] we show that virtual screening followed by synthesis and testing leads to several new NMDA glycine site ligands. Both ligand binding assays and functional investigations reveal that the identified ligands interact with the glycine binding site of the NDMA receptors, inhibiting receptor function by direct competition with glycine. The crystal structure of the NMDA receptor glycine site was recently reported. [4] Glycine is bound through a series of hydrogen bonds at the bottom of a narrow channel, leaving limited free space. The known NMDA glycine site ligands are indeed very small analogues of glycine, such as d-alanine and dserine, [5] d-cycloserine, [6] and small cyclic amino acids, [7] sug