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- W3011092337 endingPage "33" @default.
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- W3011092337 abstract "Allosteric modulation of GPCRs, especially metabotropic glutamate (mGlu) receptors, has become an important strategy for drug discovery. Positive and negative allosteric modulators (PAM, NAM) are widely reported for the mGlu receptor family with leads mostly originating by high-throughput screening followed by iterative medicinal chemistry. The progression of the field from mutagenesis and homology modeling to elaborate structure-enabled drug discovery is described. We detail how computational methods have delivered new chemical matter and revealed the functional details of PAM and NAM activity. The breakthrough in mGlu receptor 7-transmembrane (7TM) crystal structures enabled recent combined modeling and experimental studies to confirm common binding sites, interactions and the origins of ligand effect on functional activity. Focusing on allosteric modulation of the mGlu2 and mGlu5 receptors, similarities are seen that still accommodate the known differences in binding sites and SAR. This work reveals the promise of a methodical computational approach built upon deep analysis of 7TM receptor simulations and interpretation of results in the context of our current understanding of receptor function. A crucial aspect was the close collaboration between modeling and experiment necessary to build and interrogate the hypotheses." @default.
- W3011092337 created "2020-03-23" @default.
- W3011092337 creator A5022201149 @default.
- W3011092337 creator A5046444163 @default.
- W3011092337 creator A5059097965 @default.
- W3011092337 creator A5078699014 @default.
- W3011092337 date "2020-01-01" @default.
- W3011092337 modified "2023-10-16" @default.
- W3011092337 title "The computational modeling of allosteric modulation of metabotropic glutamate receptors" @default.
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