Binding of a positive allosteric modulator CDPPB to metabotropic glutamate receptor type 5 (mGluR5) probed by all-atom molecular dynamics simulations

Abstract

Positive allosteric modulators (PAMs) of metabotropic glutamate receptor type 5 (mGluR5) potentiate positive receptor response and may be effective for the treatment of schizophrenia and cognitive disorders. Although crystal structures of mGluR5 complexed with the negative allosteric modulators (NAMs) are available, no crystal structure of mGluR5 complexed with PAM has been reported to date. Thus, conformational changes associated with the binding of PAMs to mGluR5 remain elusive. Here, a PAM CDPPB, and two NAMs MTEP and MFZ10-7 used as a negative control, were docked to the crystal structure. The docked complexes were submitted to molecular dynamics simulations to examine the activation of the PAM system. An MM/GBSA binding energy calculation was performed to estimate binding strength. Furthermore, molecular switch analysis was done to get insights into conformational changes of the receptor. The PAM CDPPB displays a stronger binding affinity for mGluR5 and induces conformational changes. Also, a salt bridge between TM3 and TM7, corresponding to the ionic lock switch in class A GPCRs is found to be broken. The PAM-induced receptor conformation is more like the agonist-induced conformation than the antagonist-induced conformation, suggesting that PAM works by inducing conformation change and stabilizing the active receptor conformation.

Keywords: MD simulation; Metabotropic glutamate receptor type 5 (mGluR5); Negative allosteric modulators (NAMs); PAM CDPPB; Positive allosteric modulators (PAMs).