Virtual Screening and Molecular Dynamics Study of Potential Negative Allosteric Modulators of mGluR1 from Chinese Herbs.

Ludi Jiang,Xianbao Zhang,Liansheng Qiao,Yusu He,Xi Chen,Yanling Zhang,Gongyu Li,Yuhong Xiang

doi:10.3390/molecules200712769

Abstract

The metabotropic glutamate subtype 1 (mGluR1), a member of the metabotropic glutamate receptors, is a therapeutic target for neurological disorders. However, due to the lower subtype selectivity of mGluR1 orthosteric compounds, a new targeted strategy, known as allosteric modulators research, is needed for the treatment of mGluR1-related diseases. Recently, the structure of the seven-transmembrane domain (7TMD) of mGluR1 has been solved, which reveals the binding site of allosteric modulators and provides an opportunity for future subtype-selectivity drug design. In this study, a series of computer-aided drug design methods were utilized to discover potential mGluR1 negative allosteric modulators (NAMs). Pharmacophore models were constructed based on three different structure types of mGluR1 NAMs. After validation using the built-in parameters and test set, the optimal pharmacophore model of each structure type was selected and utilized as a query to screen the Traditional Chinese Medicine Database (TCMD). Then, three different hit lists of compounds were obtained. Molecular docking was used based on the latest crystal structure of mGluR1-7TMD to further filter these hits. As a compound with high QFIT and LibDock Score was preferred, a total of 30 compounds were retained. MD simulation was utilized to confirm the stability of potential compounds binding. From the computational results, thesinine-4ʹ-O-β-d-glucoside, nigrolineaxanthone-P and nodakenin might exhibit negative allosteric moderating effects on mGluR1. This paper indicates the applicability of molecular simulation technologies for discovering potential natural mGluR1 NAMs from Chinese herbs.

Highlights

G protein-coupled receptors (GPCRs) are seven transmembrane proteins, which contain the largest class of drug targets and almost take part in every physiological process in the human body
This work first attempted to build three pharmacophore models based on the different structure types of mGluR1 negative allosteric modulators (NAMs)
The models were used for the Traditional Chinese Medicine Database (TCMD) virtual screening

Summary

Introduction

G protein-coupled receptors (GPCRs) are seven transmembrane proteins, which contain the largest class of drug targets and almost take part in every physiological process in the human body. According to their functional similarity and sequence homology, GPCRs can be divided into six classes: class A, B, C, D, E and F [1,2]. The key residues in the orthosteric binding sites of mGluR1 and mGluR5 are 100% conserved, suggesting that subtype selectivity would be very difficult to achieve [5] This problem can be overcome by developing allosteric modulators that act on alternative binding sites. The three dimensional structure of mGluR5 was constructed based on this structure and novel mGluR5 PAMs were successfully found [14,15]

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