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GRID-independent molecular descriptor analysis and molecular docking studies to mimic the binding hypothesis of γ-aminobutyric acid transporter 1 (GAT1) inhibitors.
PeerJ 2019; 7:e6283P

Abstract

Background

The γ-aminobutyric acid (GABA) transporter GAT1 is involved in GABA transport across the biological membrane in and out of the synaptic cleft. The efficiency of this Na+ coupled GABA transport is regulated by an electrochemical gradient, which is directed inward under normal conditions. However, in certain pathophysiological situations, including strong depolarization or an imbalance in ion homeostasis, the GABA influx into the cytoplasm is increased by re-uptake transport mechanism. This mechanism may lead to extra removal of extracellular GABA which results in numerous neurological disorders such as epilepsy. Thus, small molecule inhibitors of GABA re-uptake may enhance GABA activity at the synaptic clefts.

Methods

In the present study, various GRID-independent molecular descriptor (GRIND) models have been developed to shed light on the 3D structural features of human GAT1 (hGAT1) inhibitors using nipecotic acid and N-diarylalkenyl piperidine analogs. Further, a binding hypothesis has been developed for the selected GAT1 antagonists by molecular docking inside the binding cavity of hGAT1 homology model.

Results

Our results indicate that two hydrogen bond acceptors, one hydrogen bond donor and one hydrophobic region at certain distances from each other play an important role in achieving high inhibitory potency against hGAT1. Our docking results elucidate the importance of the COOH group in hGAT1 antagonists by considering substitution of the COOH group with an isoxazol ring in compound 37, which subsequently leads to a three order of magnitude decrease in biological activity of 37 (IC50 = 38 µM) as compared to compound 1 (IC50 = 0.040 µM).

Discussion

Our docking results are strengthened by the structure activity relationship of the data series as well as by GRIND models, thus providing a significant structural basis for understanding the binding of antagonists, which may be useful for guiding the design of hGAT1 inhibitors.

Authors+Show Affiliations

Research Center for Modeling and Simulation (RCMS), National University of Sciences and Technology (NUST), Islamabad, Federal, Pakistan.Research Center for Modeling and Simulation (RCMS), National University of Sciences and Technology (NUST), Islamabad, Federal, Pakistan.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30723616

Citation

Zafar, Sadia, and Ishrat Jabeen. "GRID-independent Molecular Descriptor Analysis and Molecular Docking Studies to Mimic the Binding Hypothesis of Γ-aminobutyric Acid Transporter 1 (GAT1) Inhibitors." PeerJ, vol. 7, 2019, pp. e6283.
Zafar S, Jabeen I. GRID-independent molecular descriptor analysis and molecular docking studies to mimic the binding hypothesis of γ-aminobutyric acid transporter 1 (GAT1) inhibitors. PeerJ. 2019;7:e6283.
Zafar, S., & Jabeen, I. (2019). GRID-independent molecular descriptor analysis and molecular docking studies to mimic the binding hypothesis of γ-aminobutyric acid transporter 1 (GAT1) inhibitors. PeerJ, 7, pp. e6283. doi:10.7717/peerj.6283.
Zafar S, Jabeen I. GRID-independent Molecular Descriptor Analysis and Molecular Docking Studies to Mimic the Binding Hypothesis of Γ-aminobutyric Acid Transporter 1 (GAT1) Inhibitors. PeerJ. 2019;7:e6283. PubMed PMID: 30723616.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - GRID-independent molecular descriptor analysis and molecular docking studies to mimic the binding hypothesis of γ-aminobutyric acid transporter 1 (GAT1) inhibitors. AU - Zafar,Sadia, AU - Jabeen,Ishrat, Y1 - 2019/01/31/ PY - 2018/10/11/received PY - 2018/12/14/accepted PY - 2019/2/7/entrez PY - 2019/2/7/pubmed PY - 2019/2/7/medline KW - 3D QSAR KW - Docking KW - GABA transporter 1 (GAT1) KW - GRIND model KW - Structure–activity relationship (SAR) KW - Tiagabine KW - hGAT1 inhibitors SP - e6283 EP - e6283 JF - PeerJ JO - PeerJ VL - 7 N2 - Background: The γ-aminobutyric acid (GABA) transporter GAT1 is involved in GABA transport across the biological membrane in and out of the synaptic cleft. The efficiency of this Na+ coupled GABA transport is regulated by an electrochemical gradient, which is directed inward under normal conditions. However, in certain pathophysiological situations, including strong depolarization or an imbalance in ion homeostasis, the GABA influx into the cytoplasm is increased by re-uptake transport mechanism. This mechanism may lead to extra removal of extracellular GABA which results in numerous neurological disorders such as epilepsy. Thus, small molecule inhibitors of GABA re-uptake may enhance GABA activity at the synaptic clefts. Methods: In the present study, various GRID-independent molecular descriptor (GRIND) models have been developed to shed light on the 3D structural features of human GAT1 (hGAT1) inhibitors using nipecotic acid and N-diarylalkenyl piperidine analogs. Further, a binding hypothesis has been developed for the selected GAT1 antagonists by molecular docking inside the binding cavity of hGAT1 homology model. Results: Our results indicate that two hydrogen bond acceptors, one hydrogen bond donor and one hydrophobic region at certain distances from each other play an important role in achieving high inhibitory potency against hGAT1. Our docking results elucidate the importance of the COOH group in hGAT1 antagonists by considering substitution of the COOH group with an isoxazol ring in compound 37, which subsequently leads to a three order of magnitude decrease in biological activity of 37 (IC50 = 38 µM) as compared to compound 1 (IC50 = 0.040 µM). Discussion: Our docking results are strengthened by the structure activity relationship of the data series as well as by GRIND models, thus providing a significant structural basis for understanding the binding of antagonists, which may be useful for guiding the design of hGAT1 inhibitors. SN - 2167-8359 UR - https://www.unboundmedicine.com/medline/citation/30723616/GRID-independent_molecular_descriptor_analysis_and_molecular_docking_studies_to_mimic_the_binding_hypothesis_of_γ-aminobutyric_acid_transporter_1_(GAT1)_inhibitors L2 - https://doi.org/10.7717/peerj.6283 DB - PRIME DP - Unbound Medicine ER -
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