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A comprehensive in silico investigation into the nsSNPs of Drd2 gene predicts significant functional consequences in dopamine signaling and pharmacotherapy

View ORCID ProfileSamia Sultana Lira, View ORCID ProfileIshtiaque Ahammad
doi: https://doi.org/10.1101/2021.06.11.448090
Samia Sultana Lira
1Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka 1000, Bangladesh
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Ishtiaque Ahammad
2Bioinformatics Division, National Institute of Biotechnology, Ganakbari, Ashulia, Savar, Dhaka 1349, Bangladesh
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  • For correspondence: ishtiaque.ahammad@northsouth.edu ishtiaquebioinfo@nib.gov.bd
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Abstract

DRD2 is a neuronal cell surface protein involved in brain development and function. Variations in the Drd2 gene have clinical significance since DRD2 is a pharmacotherapeutic target for treating psychiatric disorders like ADHD and schizophrenia. Despite numerous studies on the disease association of single nucleotide polymorphisms (SNPs) in the intronic regions, investigation into the coding regions is surprisingly limited. In this study, we aimed at identifying potential functionally and pharmaco-therapeutically deleterious non-synonymous SNPs of Drd2. A wide array of bioinformatics tools was used to evaluate the impact of nsSNPs on protein structure and functionality. Out of 260 nsSNPs retrieved from the dbSNP database, initially 9 were predicted as deleterious by 15 tools. Upon further assessment of their domain association, conservation profile, homology models and inter-atomic interaction, the mutant F389V was considered as the most impactful. In-depth analysis of F389V through Molecular Docking and Dynamics Simulation revealed a decline in affinity for its native agonist dopamine and an increase in affinity for the antipsychotic drug risperidone. Remarkable alterations in binding interactions and stability of the protein-ligand complex in simulated physiological conditions were also noted. These findings will improve our understanding of the consequence of nsSNPs in disease-susceptibility and therapeutic efficacy.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted June 13, 2021.
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A comprehensive in silico investigation into the nsSNPs of Drd2 gene predicts significant functional consequences in dopamine signaling and pharmacotherapy
Samia Sultana Lira, Ishtiaque Ahammad
bioRxiv 2021.06.11.448090; doi: https://doi.org/10.1101/2021.06.11.448090
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A comprehensive in silico investigation into the nsSNPs of Drd2 gene predicts significant functional consequences in dopamine signaling and pharmacotherapy
Samia Sultana Lira, Ishtiaque Ahammad
bioRxiv 2021.06.11.448090; doi: https://doi.org/10.1101/2021.06.11.448090

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