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Cited by 131Computational Drug Discovery MethodsProtein Structure and DynamicsProtein Interaction Studies and Fluorescence Analysis

Understanding the challenges of protein flexibility in drug design.

Antunes, Dinler A, Devaurs, Didier, Kavraki, Lydia E·2015·Expert Opinion on Drug Discovery
DOI 10.1517/17460441.2015.1094458
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Abstract

INTRODUCTION: Protein-ligand interactions play key roles in various metabolic pathways, and the proteins involved in these interactions represent major targets for drug discovery. Molecular docking is widely used to predict the structure of protein-ligand complexes, and protein flexibility stands out as one of the most important and challenging issues for binding mode prediction. Various docking methods accounting for protein flexibility have been proposed, tackling problems of ever-increasing dimensionality. AREAS COVERED: This paper presents an overview of conformational sampling methods treating target flexibility during molecular docking. Special attention is given to approaches considering full protein flexibility. Contrary to what is frequently done, this review does not rely on classical biomolecular recognition models to classify existing docking methods. Instead, it applies algorithmic considerations, focusing on the level of flexibility accounted for. This review also discusses the diversity of docking applications, from virtual screening (VS) of small drug-like compounds to geometry prediction (GP) of protein-peptide complexes. EXPERT OPINION: Considering the diversity of docking methods presented here, deciding which one is the best at treating protein flexibility depends on the system under study and the research application. In VS experiments, ensemble docking can be used to implicitly account for large-scale conformational changes, and selective docking can additionally consider local binding-site rearrangements. In other cases, on-the-fly exploration of the whole protein-ligand complex might be needed for accurate GP of the binding mode. Among other things, future methods are expected to provide alternative binding modes, which will better reflect the dynamic nature of protein-ligand interactions.

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  • Despite many efforts to include protein flexibility in VS experiments, the complex and multifactorial framework of flexible protein-ligand binding is still a great challenge.

    “Despite the many efforts made to include the protein flexibility in VS experiments, the complex and multifactorial framework of flexible protein–ligand binding is still a great challenge (Bottegoni et al., 2011; Nunes-Alves and Arantes, 2014; Antunes et al., 2015; Buonfiglio et al., 2015; Kong et al., 2018).”

    From Empirical scoring functions for structure-based virtual screening: applications, critical aspects, and challenges (2018) · cites this paper as Antunes et al., 2015

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Authors
Antunes, D. A., Devaurs, D., & Kavraki, L. E.
Affiliations
Rice University (US)
ORCID
Venue
Expert Opinion on Drug Discovery
Publisher
Informa UK Limited
Published
2015-09-28
Volume
10
Issue
12
Pages
1301-1313
ISSN
  • 1746-0441 (ISSN-L)
  • 1746-045X
DOI
10.1517/17460441.2015.1094458
OpenAlex
W1881444267
Cited by
131
References
151
Citations by year
2026: 12 · 2025: 16 · 2024: 10 · 2023: 8 · 2022: 13 · 2021: 12 · 2020: 11 · 2019: 17 · 2018: 11 · 2017: 15 · 2016: 6
FWCI
1.14
Type
journal article
Language
en
Open access
closed
Locations
  • Expert Opinion on Drug Discovery (publishedVersion)
  • PubMed (publishedVersion)
  • Rice Research Repository (Rice University) (acceptedVersion)
  • Rice Research Repository (Rice University) (submittedVersion)
Funders
  • National Science Foundation
  • Conselho Nacional de Desenvolvimento Científico e Tecnológico
  • National Institute of General Medical Sciences (P41GM103311)
Topics
  • Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Interaction Studies and Fluorescence Analysis
Keywords
protein flexibility, molecular docking, protein-ligand interactions, conformational sampling, ensemble docking, binding mode prediction, protein-peptide complex, virtual screening, protein conformational change
MeSH terms
Algorithms, Binding Sites, Humans, Ligands, Models, Molecular, Peptides, Protein Binding, Proteins, Drug Design, Drug Discovery, Molecular Docking Simulation

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