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Advancing NMDA Receptor Physiology by Integrating Multiple Approaches.

ABSTRACT: NMDA receptors (NMDARs) are ion channels activated by the excitatory neurotransmitter glutamate and are essential to all aspects of brain function, including learning and memory formation. Missense mutations distributed throughout NMDAR subunits have been associated with an array of neurological disorders. Recent structural, functional, and computational studies have generated many insights into the activation process connecting glutamate binding to ion-channel opening, which is central to NMDAR physiology and pathophysiology. The field appears poised for breakthroughs, including the exciting prospect of resolving the conformations and energetics of elementary steps in the activation process, and atomic-level modeling of the effects of missense mutations on receptor function. The most promising strategy going forward is through strong integration of multiple approaches.

SUBMITTER: Zhou HX

PROVIDER: S-EPMC5339030 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Advancing NMDA Receptor Physiology by Integrating Multiple Approaches.

Zhou Huan-Xiang HX Wollmuth Lonnie P LP

Trends in neurosciences 20170208 3

NMDA receptors (NMDARs) are ion channels activated by the excitatory neurotransmitter glutamate and are essential to all aspects of brain function, including learning and memory formation. Missense mutations distributed throughout NMDAR subunits have been associated with an array of neurological disorders. Recent structural, functional, and computational studies have generated many insights into the activation process connecting glutamate binding to ion-channel opening, which is central to NMDAR ...[more]

PMID: 28187950

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Project description:The glutamate-gated ion channels known as N-methyl-d-aspartate receptors (NMDARs) are important for both normal and pathological brain function. Subunit-selective antagonists have high therapeutic promise since many pathological conditions involve NMDAR over activation, although few clinical successes have been reported. Allosteric inhibitors of GluN2B-containing receptors are among the most potential NMDAR targeting drugs. Since the discovery of ifenprodil, a variety of GluN2B-selective compounds have been discovered, each with remarkably unique structural motifs. These results expand the allosteric and pharmacolog-ical spectrum of NMDARs and provide a new structural basis for the development of next-generation GluN2B antagonists that have therapeutic potential in brain diseases. Small molecule therapeutic inhibitors targeting NMDA have recently been developed to target CNS disorders such as Alzheimer's disease. In the current study, a cheminformatics method was used to discover potential antagonists and to identify the structural requirements for Gly/NMDA antagonism. In this case we have created a useful pharmacophore model with solid statistical values. Through pharmacophore mapping, the verified model was used to filter out virtual matches from the ZINC database. Assessing receptor-ligand binding mechanisms and affinities used molecular docking. To find the best hits, the GlideScore and the interaction of molecules with important amino acids were considered essential features. We found some molecular inhibitors, namely, ZINC13729211, ZINC07430424, ZINC08614951, ZINC60927204, ZINC12447511, and ZINC18889258 with high binding affinity using computational methods. The molecules in our studies showed characteristics such as good stability, hydrogen bonding and higher binding affinities in the solvation-based assessment method than ifenprodil with acceptable ADMET profile. Moreover, these six leads have been proposed as potential new perspectives for exploring potent Gly/NMDA receptor antagonists. In addition, it can be tested in the laboratory for potential therapeutic strategies for both in vitro and in vivo research.

Project description:Sufficient data refer to the relevant prevalence of sound exposure by mixed traffic sources in many nations. Furthermore, consideration of the potential effects of combined sound exposure is required in legal procedures such as environmental health impact assessments. Nevertheless, current practice still uses single exposure response functions. It is silently assumed that those standard exposure-response curves accommodate also for mixed exposures-although some evidence from experimental and field studies casts doubt on this practice. The ALPNAP-study population (N = 1641) shows sufficient subgroups with combinations of rail-highway, highway-main road and rail-highway-main road sound exposure. In this paper we apply a few suggested approaches of the literature to investigate exposure-response curves and its major determinants in the case of exposure to multiple traffic sources. Highly/moderate annoyance and full scale mean annoyance served as outcome. The results show several limitations of the current approaches. Even facing the inherent methodological limitations (energy equivalent summation of sound, rating of overall annoyance) the consideration of main contextual factors jointly occurring with the sources (such as vibration, air pollution) or coping activities and judgments of the wider area soundscape increases the variance explanation from up to 8% (bivariate), up to 15% (base adjustments) up to 55% (full contextual model). The added predictors vary significantly, depending on the source combination. (e.g., significant vibration effects with main road/railway, not highway). Although no significant interactions were found, the observed additive effects are of public health importance. Especially in the case of a three source exposure situation the overall annoyance is already high at lower levels and the contribution of the acoustic indicators is small compared with the non-acoustic and contextual predictors. Noise mapping needs to go down to levels of 40 dBA,Lden to ensure the protection of quiet areas and prohibit the silent "filling up" of these areas with new sound sources. Eventually, to better predict the annoyance in the exposure range between 40 and 60 dBA and support the protection of quiet areas in city and rural areas in planning sound indicators need to be oriented at the noticeability of sound and consider other traffic related by-products (air quality, vibration, coping strain) in future studies and environmental impact assessments.

Dataset Information

Advancing NMDA Receptor Physiology by Integrating Multiple Approaches.

Publications

Advancing NMDA Receptor Physiology by Integrating Multiple Approaches.

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