7TM X-ray structures for class C GPCRs as new drug-discovery tools. 1. mGluR5
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- 作者：Sid Topiol ; Sid.Topiol@gmail.com" class="auth_mail" title="E-mail the corresponding author ; Michael Sabio
- 关键词：Structure-based drug design ; Computer-aided drug discovery ; Metabotropic glutamate receptors (mGluRs) ; Mavoglurant ; Docking ; X-ray structure ; Negative allosteric modulators (NAMs) ; Positive allosteric modulators (PAMs)
- 刊名：Bioorganic & Medicinal Chemistry Letters
- 出版年：2016
- 出版时间：15 January 2016
- 年：2016
- 卷：26
- 期：2
- 页码：484-494
- 全文大小：3412 K
文摘
We illustrate, with a focus on mGluR5, how the recently published, first X-ray structures of mGluR 7TM domains, specifically those of mGluR1 and mGluR5 complexed with negative allosteric modulators (NAMs), will begin to influence ligand- (e.g., drug- or sweetener-) discovery efforts involving class C GPCRs. With an extensive docking study allowing full ligand flexibility and full side chain flexibility of all residues in the ligand-binding cavity, we have predicted and analyzed the binding modes of a variety of structurally diverse mGluR5 NAM ligands, showing how the X-ray structures serve to effectively rationalize each ligand’s binding characteristics. We demonstrated that the features that are inherent in our earlier overlay model are preserved in the protein structure-based docking models. We identified structurally diverse compounds, which potentially act as mGluR NAMs, and revealed binding-site differences by performing high-throughput docking using a database of approximately six million structures of commercially available compounds and the mGluR1 and mGluR5 X-ray structures. By comparing the 7TM domains of the mGluR5 and mGluR1 X-rays structures, we identified selectivity factors within group I of the mGluRs. Similarly, using homology models that we built for mGluR2 and mGluR4, we have identified the factors leading to the selectivity between group I and groups II and III for ligands occupying the deepest portion of the mGluR5 binding cavity. Finally, we have proposed a structure-based explanation of the pharmacological switching within a set of positive allosteric modulators (PAMs) and their corresponding, very close NAM analogs.