ArticleChemical science2020
Adapting free energy perturbation simulations for large macrocyclic ligands: how to dissect contributions from direct binding and free ligand flexibility.
Article in Chemical science, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed.
- MDFit: automated molecular simulations workflow enables high throughput assessment of ligands-protein dynamics.Journal of computer-aided molecular design · 2024Article
- Monoclonal antibody designed for SARS-nCoV-2 spike protein of receptor binding domain on antigenic targeted epitopes for inhibition to prevent viral entry.Molecular diversity · 2023Article
- Computational approaches for the design of modulators targeting protein-protein interactions.Expert opinion on drug discovery · 2023Review
- pIChemiSt ─ Free Tool for the Calculation of Isoelectric Points of Modified Peptides.Journal of chemical information and modeling · 2023Article
- The Use of Molecular Dynamics Simulation Method to Quantitatively Evaluate the Affinity between HBV Antigen T Cell Epitope Peptides and HLA-A Molecules.International journal of molecular sciences · 2022Article
- Single-chain tandem macrocyclic peptides as a scaffold for growth factor and cytokine mimetics.Communications biology · 2022Article
- Anchor extension: a structure-guided approach to design cyclic peptides targeting enzyme active sites.Nature communications · 2021Article
- Peptide-based inhibitors of protein-protein interactions: biophysical, structural and cellular consequences of introducing a constraint.Chemical science · 2021Review
- Computational Modeling as a Tool to Investigate PPI: From Drug Design to Tissue Engineering.Frontiers in molecular biosciences · 2021Review
- Stapled Peptides as HIF-1α/p300 Inhibitors: Helicity Enhancement in the Bound State Increases Inhibitory Potency.Chemistry (Weinheim an der Bergstrasse, Germany) · 2020Article
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Authors and funding
6 authors.
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Abstract
Large and flexible ligands gain increasing interest in the development of bioactive agents. They challenge the applicability of computational ligand optimization strategies originally developed for small molecules. Free energy perturbation (FEP) is often used for predicting binding affinities of small molecule ligands, however, its use for more complex ligands remains limited. Herein, we report the structure-based design of peptide macrocycles targeting the protein binding site of human adaptor protein 14-3-3. We observe a surprisingly strong dependency of binding affinities on relatively small variations in substituent size. FEP was performed to rationalize observed trends. To account for insufficient convergence of FEP, restrained calculations were performed and complemented with extensive REST MD simulations of the free ligands. These calculations revealed that changes in affinity originate both from altered direct interactions and conformational changes of the free ligand. In addition, MD simulations provided the basis to rationalize unexpected trends in ligand lipophilicity. We also verified the anticipated interaction site and binding mode for one of the high affinity ligands by X-ray crystallography. The introduced fully-atomistic simulation protocol can be used to rationalize the development of structurally complex ligands which will support future ligand maturation efforts.
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