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.
Highlights
DRD2 is a neuronal cell surface protein involved in brain development and function
With an aim to investigate the damaging effect of Drd[2] nonsynonymous SNPs (nsSNPs) on disease predisposition and treatment responsiveness, in this study, we focused on the DRD2 protein structural and functional impairment upon mutation
Since the scope of the study is limited to nsSNPs of Drd[2], only nsSNPs were subjected to subsequent analysis
Summary
DRD2 is a neuronal cell surface protein involved in brain development and function. Variations in the Drd[2] gene have clinical significance since DRD2 is a pharmacotherapeutic target for treating psychiatric disorders like ADHD and schizophrenia. Computational screening of SNPs to shorten down the number of potential pathogenic ones is an essential step prior to experimental mutation analysis In this context, several in silico approaches have been largely utilized in the recent decade to predict the structural and functional influence of deleterious nsSNP in genes of interest. With an aim to investigate the damaging effect of Drd[2] nsSNPs on disease predisposition and treatment responsiveness, in this study, we focused on the DRD2 protein structural and functional impairment upon mutation For this purpose, a number of bioinformatics tools were employed to identify the most deleterious nsSNPs in Drd[2] and evaluate their effect on the gene product. Following analyses including conservation profile, domain position, post-translational modifications, we performed molecular docking and dynamics simulation for better understating of mutation impact in physiological condition
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