Format

Send to

Choose Destination
See comment in PubMed Commons below
J R Soc Interface. 2012 Jul 7;9(72):1409-37. doi: 10.1098/rsif.2011.0843. Epub 2012 May 2.

Bioinformatics and variability in drug response: a protein structural perspective.

Author information

1
Department of Bioengineering, Stanford University, Stanford, CA, USA.

Abstract

Marketed drugs frequently perform worse in clinical practice than in the clinical trials on which their approval is based. Many therapeutic compounds are ineffective for a large subpopulation of patients to whom they are prescribed; worse, a significant fraction of patients experience adverse effects more severe than anticipated. The unacceptable risk-benefit profile for many drugs mandates a paradigm shift towards personalized medicine. However, prior to adoption of patient-specific approaches, it is useful to understand the molecular details underlying variable drug response among diverse patient populations. Over the past decade, progress in structural genomics led to an explosion of available three-dimensional structures of drug target proteins while efforts in pharmacogenetics offered insights into polymorphisms correlated with differential therapeutic outcomes. Together these advances provide the opportunity to examine how altered protein structures arising from genetic differences affect protein-drug interactions and, ultimately, drug response. In this review, we first summarize structural characteristics of protein targets and common mechanisms of drug interactions. Next, we describe the impact of coding mutations on protein structures and drug response. Finally, we highlight tools for analysing protein structures and protein-drug interactions and discuss their application for understanding altered drug responses associated with protein structural variants.

PMID:
22552919
PMCID:
PMC3367825
DOI:
10.1098/rsif.2011.0843
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Support Center