Cited by 56Computational Drug Discovery MethodsProtein Structure and DynamicsChemical Synthesis and Analysis

Revolutionizing peptide‐based drug discovery: Advances in the post‐AlphaFold era

Open access
Chang, Liwei, Mondal, Arup, Singh, Bhumika, Martínez‐Noa, Yisel, Perez, Alberto·2024·WIREs Computational Molecular Science

Abstract

Peptide‐based drugs offer high specificity, potency, and selectivity. However, their inherent flexibility and differences in conformational preferences between their free and bound states create unique challenges that have hindered progress in effective drug discovery pipelines. The emergence of AlphaFold (AF) and Artificial Intelligence (AI) presents new opportunities for enhancing peptide‐based drug discovery. We explore recent advancements that facilitate a successful peptide drug discovery pipeline, considering peptides' attractive therapeutic properties and strategies to enhance their stability and bioavailability. AF enables efficient and accurate prediction of peptide‐protein structures, addressing a critical requirement in computational drug discovery pipelines. In the post‐AF era, we are witnessing rapid progress with the potential to revolutionize peptide‐based drug discovery such as the ability to rank peptide binders or classify them as binders/non‐binders and the ability to design novel peptide sequences. However, AI‐based methods are struggling due to the lack of well‐curated datasets, for example to accommodate modified amino acids or unconventional cyclization. Thus, physics‐based methods, such as docking or molecular dynamics simulations, continue to hold a complementary role in peptide drug discovery pipelines. Moreover, MD‐based tools offer valuable insights into binding mechanisms, as well as the thermodynamic and kinetic properties of complexes. As we navigate this evolving landscape, a synergistic integration of AI and physics‐based methods holds the promise of reshaping the landscape of peptide‐based drug discovery. This article is categorized under: Structure and Mechanism > Computational Biochemistry and Biophysics Molecular and Statistical Mechanics > Molecular Interactions Software > Molecular Modeling

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  • AlphaFold and other structure prediction technologies have transformed peptide study by providing precise three-dimensional representations of peptide conformations and interactions with target proteins.

    “The AlphaFold and other structure prediction technologies have also transformed the study of peptides by providing precise three-dimensional representations of peptide conformations and the interactions of peptides with their target proteins.”

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Research works printed but not linked: 1

  1. Tsaban T, Varga JK, Avraham O, Ben-Aharon Z, Khramushin A, Schueler-Furman O. Harnessing protein folding neural networks for peptide-protein docking. Nat Commun. 2022;13:176.

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Authors
Chang, L., Mondal, A., Singh, B., Martínez‐Noa, Y., & Perez, A.
Affiliations
  • University of Florida (US)
  • Department of Chemistry University of Florida Gainesville Florida USA
Venue
WIREs Computational Molecular Science
Publisher
Wiley
Published
2023-11-12
Volume
14
Issue
1
ISSN
  • 1759-0876 (ISSN-L)
  • 1759-0884
OpenAlex
W4388616875
Cited by
56
References
117
Citations by year
2026: 23 · 2025: 24 · 2024: 9
FWCI
8.02
Type
journal article
Language
en
Open access
Locations
  • Wiley Interdisciplinary Reviews Computational Molecular Science (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute of General Medical Sciences (1 R01GM149646‐01)
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 › Chemical Synthesis and Analysis
Keywords
peptide therapeutics, peptide drug discovery, AlphaFold, artificial intelligence in drug discovery, peptide design, peptide stability, bioavailability, molecular docking, molecular dynamics simulation, binding mechanism, modified amino acids, cyclic peptides

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