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Related Concept Videos

Pharmacogenetic Phenotypes: Alterations in Pharmacokinetics, Drug Targets and Biologic Milieu01:29

Pharmacogenetic Phenotypes: Alterations in Pharmacokinetics, Drug Targets and Biologic Milieu

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Genetic variations significantly influence drug response through pharmacokinetics, receptor interactions, and biologic milieu modifications. Pharmacokinetic alterations impact drug metabolism and clearance, affecting efficacy and toxicity. Variants in drug-metabolizing enzymes, such as CYP2C9 and CYP2C19, alter drug activation and elimination. For example, CYP2C9 loss-of-function variants require lower warfarin doses to prevent excessive bleeding, while CYP2C19 variants reduce clopidogrel...
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Pharmacogenetics of Drug Metabolism: Overview01:27

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Genetic polymorphism in drug metabolism is crucial to the inter-individual variability observed in drug responses. Drug metabolism primarily involves the chemical modification of drugs and other xenobiotics to enhance their elimination by increasing their polarity. Two main classes of enzymes mediate this biotransformation process: Phase I enzymes, primarily cytochrome P450s, catalyze oxidation and reduction reactions, while other enzymes, such as esterases, mediate hydrolysis, and Phase II...
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Mania and Antimanic Drugs: Overview01:24

Mania and Antimanic Drugs: Overview

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Mania, a psychological condition characterized by elevated mood, increased energy, and reduced sleep need, is part of the bipolar disorder cycle. The exact cause of mania isn't entirely known, but it is thought to be a combination of genetic, environmental, and neurological factors. Bipolar disorder involves alternating manic and depressive episodes. Mood stabilizers like lithium, antipsychotics, and anticonvulsants help manage these episodes. Lithium carbonate is particularly effective as...
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Principles of Pharmacogenetics: Types of Genetic Variants01:27

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The human genome is over 99.9% identical between individuals, yet genetic differences exist at millions of bases. The human genome contains approximately 3 million variant positions per individual, many of which are heterozygous, contributing to genetic diversity and individual traits. Genetic variations include single-nucleotide polymorphisms (SNPs), insertions, deletions, and copy number variations (CNVs).SNPs, the most common variation, involve single-base changes in DNA. These can be...
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Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase01:11

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Genetic polymorphisms in drug targets have emerged as critical determinants of interindividual variability in drug response and toxicity. Pharmacogenomic investigations increasingly focus on identifying these variations to personalize and optimize therapeutic interventions. A drug target may be a receptor, enzyme, or signaling protein involved in pharmacologic responses or disease-related pathways. While early pharmacogenetic studies focused primarily on drug metabolism, current research...
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Human Genetics01:28

Human Genetics

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Human genetics provides a profound framework for understanding the interplay between genetic predispositions and human psychology. At the heart of this discipline lies the study of how genes influence physical traits, behaviors, and susceptibility to diseases. Each person carries a unique genetic code that subtly or significantly shapes their psychological and behavioral landscape.
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Genetic Polymorphisms Associated with Lithium Response in Bipolar Disorder: An Integrative Review and In Silico

Ovinuchi Ejiohuo1,2, Aleksandra Szczepankiewicz2,3

  • 1Department of Psychiatric Genetics, Poznan University of Medical Sciences, Rokietnicka 8, 60-806 Poznan, Poland.

Pharmaceuticals (Basel, Switzerland)
|March 28, 2026
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Summary

Genetic variations in neuroplasticity and HPA axis genes influence lithium response in bipolar disorder by altering protein interactions. These findings offer a structural basis for understanding pharmacogenetic variability in treatment.

Keywords:
bipolar disordergenetic polymorphismin silicolithium responseprotein–protein interaction

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Area of Science:

  • Pharmacogenetics
  • Molecular Biology
  • Neuroscience

Background:

  • Lithium response in bipolar disorder is variable, with responders forming a distinct subgroup.
  • Pharmacogenetic studies link neuroplasticity (BDNF) and HPA axis (NR3C1) genes to lithium response.
  • The biophysical mechanisms underlying these genetic links are not well understood.

Purpose of the Study:

  • To quantify the atomic-level effects of lithium-response polymorphisms on protein-protein interaction stability and dynamics.
  • To bridge the gap between genetic associations and the biophysical mechanisms of lithium response.
  • To investigate the structural impact of BDNF rs6265 and NR3C1 rs56149945 variants.

Main Methods:

  • Generated variant sequences for BDNF rs6265 and NR3C1 rs56149945.
  • Structurally modeled proteins and analyzed BDNF-TrkB and NR3C1-FKBP5 interactions.
  • Evaluated binding affinity, interaction energetics, and conformational flexibility using computational tools (PRODIGY, HawkDock, CABS-flex).

Main Results:

  • Variant complexes showed stronger interactions and increased binding affinity (e.g., BDNF-TrkB: -15.1 kcal/mol, NR3C1-FKBP5: -18.8 kcal/mol).
  • Computational analyses confirmed enhanced stability for variant protein complexes.
  • Structural analysis revealed preserved global protein folds with localized interface adjustments.

Conclusions:

  • Lithium-response polymorphisms modulate protein-protein interaction stability.
  • These changes occur while maintaining overall protein structure.
  • Provides a structural framework for understanding genetic influences on lithium treatment response in bipolar disorder.