Addressing the Conformational Flexibility of Serine Racemase by Combining Targeted Molecular Dynamics, Conformational Sampling and Docking Studies

Abstract Serine racemase (SR) is a PLP‐dependent enzyme catalyzing the racemization of L ‐Ser into D ‐Ser, which is now recognized as an endogenous co‐agonist at the NMDA receptor complex. As indicated by available X‐ray structures, SR undergoes significant conformational changes during ligand recognition, and it is conceivable that, in addition to the reported X‐ray structures, other intermediate conformational states may have relevance in drug discovery studies. Targeted molecular dynamics (TMD) simulations are an effective tools to follow the conformational transition of a protein under the constrain of reaching a known target states. In this study we use TMD to simulate the transition between the open and closed form of SR in the presence of the endogenous substrate or an orthosteric inhibitor. The trajectories thus obtained are then clustered to collect an ensemble of intermediate conformational states. Docking of a small library of known SR inhibitors or closely related inactive analogs demonstrates that ensemble docking performs better than docking on available crystal structures, thus indicating that inclusion of conformational flexibility into ligand design strategies will be crucial for the development of new classes of SR inhibitors.