Cited by 755Protein Structure and DynamicsComputational Drug Discovery MethodsProtein Interaction Studies and Fluorescence Analysis

Implications of protein flexibility for drug discovery

Teague, Simon J.·2003·Nature Reviews Drug Discovery

Abstract

Proteins are in constant motion between different conformational states with similar energies. This has often been ignored in drug design. However, protein flexibility is fundamental to understanding the ways in which drugs exert biological effects, their binding-site location, binding orientation, binding kinetics, metabolism and transport. Protein flexibility allows increased affinity to be achieved between a drug and its target. This is crucial, because the lipophilicity and number of polar interactions allowed for an oral drug is limited by absorption, distribution, metabolism and toxicology considerations.

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Crossref · 10.1038/nrd1129

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  • Physic-based methods such as docking can be sensitive to structural error or pocket conformational changes.

    “Albeit powerful, due to their heavy dependency on atomic distances to evaluate scoring functions, these methods can be sensitive to structural error or pocket conformational changes 3 .”

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Authors
Teague, S. J.
Affiliations
AstraZeneca (United Kingdom) (GB)
Corresponding author
Teague, Simon J.
Venue
Nature Reviews Drug Discovery
Published
2003-07
Volume
2
Issue
7
Pages
527-541
ISSN
  • 1474-1776 (ISSN-L)
  • 1474-1784
OpenAlex
W1974645077
Cited by
755
References
91
Citations by year
2026: 41 · 2025: 29 · 2024: 29 · 2023: 24 · 2022: 18 · 2021: 31 · 2020: 36 · 2019: 16 · 2018: 28 · 2017: 27 · 2016: 32 · 2015: 28 · 2014: 44 · 2013: 32 · 2012: 40
FWCI
2.52
Type
journal article
Language
en
Open access
closed
Locations
  • Nature Reviews Drug Discovery (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Interaction Studies and Fluorescence Analysis
Keywords
protein flexibility, protein conformational states, drug-target binding, binding affinity, binding kinetics, binding orientation, binding sites, drug metabolism, drug transport, drug absorption, lipophilicity, polar interactions, drug design
MeSH terms
Ligands, Protein Conformation, Thermodynamics, Drug Design

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