Revolutionizing peptide‐based drug discovery: Advances in the post‐AlphaFold era
Open accessAbstract
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.”
From Navigating the potential of algal peptides: health effects, market applications, and scientific challenges (2026) · cites this paper as [211]
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Gao, Z., Tan, C., Chacón, P., et al. (2022) · arXiv (Cornell University) · doi:10.48550/arxiv.2209.12643 · Cited by 51 · see citing works
Documentation of an Imperative To Improve Methods for Predicting Membrane Protein Stability
Kroncke, B. M., Duran, A. M., Mendenhall, J. L., Meiler, J., Blume, J. D., & Sanders, C. R. (2016) · Biochemistry · doi:10.1021/acs.biochem.6b00537 · Cited by 50 · see citing works
Adaptive Markov state model estimation using short reseeding trajectories.
Wan, H., & Voelz, V. A. (2019) · Journal of Chemical Physics · doi:10.1063/1.5142457 · Cited by 49 · see citing works
InterPep2: global peptide–protein docking using interaction surface templates
Johansson-Åkhe, I., Mirabello, C., & Wallner, B. (2020) · Bioinformatics · doi:10.1093/bioinformatics/btaa005 · Cited by 47 · see citing works
Jagger, B. R., Ojha, A. A., & Amaro, R. E. (2020) · Journal of Chemical Theory and Computation · doi:10.1021/acs.jctc.0c00495 · Cited by 46 · see citing works
Folding and insertion thermodynamics of the transmembrane WALP peptide
Bereau, T., Bennett, W. F., Pfaendtner, J., Deserno, M., & Karttunen, M. (2015) · The Journal of Chemical Physics · doi:10.1063/1.4935487 · Cited by 45 · see citing works
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Using Metadynamics to Understand the Mechanism of Calmodulin/Target Recognition at Atomic Detail
Fiorin, G., Pastore, A., Carloni, P., & Parrinello, M. (2006) · Biophysical Journal · doi:10.1529/biophysj.106.086611 · Cited by 43 · see citing works
Shanker, S., & Sanner, M. F. (2023) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.3c00602 · Cited by 43 · see citing works
Towards rational computational peptide design
Chang, L., Mondal, A., & Pérez, A. (2022) · Frontiers in Bioinformatics · doi:10.3389/fbinf.2022.1046493 · Cited by 42 · see citing works
Self-citationPinaColada: peptide–inhibitor ant colony ad-hoc design algorithm
Zaidman, D., & Wolfson, H. J. (2016) · Bioinformatics · doi:10.1093/bioinformatics/btw133 · Cited by 30 · see citing works
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Graph Denoising Diffusion for Inverse Protein FoldingPreprint
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Hybrid computational methods combining experimental information with molecular dynamics
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Self-citationMELD-Path Efficiently Computes Conformational Transitions, Including Multiple and Diverse Paths
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Binding and Unbinding Pathways of Peptide Substrates on the SARS-CoV-2 3CL Protease
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Structure modeling and specificity of peptide-MHC class I interactions using geometric deep learningPreprint
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Efficient and accurate sequence generation with small-scale protein language modelsPreprint
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Peptide-MHC Structure Prediction With Mixed Residue and Atom Graph Neural NetworkPreprint
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Flagged first, then by citations
Research works printed but not linked: 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.
Cited by
Sorted by citations
Khaliq, M., Noor, Z., Moazzam, M., Saeed, F., Tul-Zohra, K., Tariq, E., Muhammad Shahbaz, H., & Khaliq, K. (2026) · Annals of Medicine · doi:10.1080/07853890.2026.2637282 · Cited by 4 · see citing works
“It is also useful in the study of the algal peptide-biomarker interactions, such as that between algal peptides and ACE (angiotensin-converting enzyme) or DPP-IV (dipeptidyl peptidase-IV) [211].”
- 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
- PMC
- PMC11052547
- 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
- bronze
- doi.org
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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