RT Journal Article
SR Electronic
T1 A comprehensive <em>in silico</em> investigation into the nsSNPs of <em>Drd2</em> gene predicts significant functional consequences in dopamine signaling and pharmacotherapy
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.06.11.448090
DO 10.1101/2021.06.11.448090
A1 Samia Sultana Lira
A1 Ishtiaque Ahammad
YR 2021
UL http://biorxiv.org/content/early/2021/06/13/2021.06.11.448090.abstract
AB 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 StatementThe authors have declared no competing interest.