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Natural Product Reports Dec 2022Covering: upto 2022Natural products have an embedded recognition of protein surfaces. They possess this property as they are produced by biosynthetic enzymes and are... (Review)
Review
Covering: upto 2022Natural products have an embedded recognition of protein surfaces. They possess this property as they are produced by biosynthetic enzymes and are substrates for one or more enzymes in the biosynthetic pathway. The inherent advantages, compared to synthetic compound libraries, is this ligand-protein binding which is, in many cases, a function of the 3-dimensional properties. Protein degradation is a recent novel therapeutic approach with several compounds now in the clinic. This review highlights the potential of PROteolysis TArgeting Chimeras (PROTACs) in the area of natural products. The approach will complement existing approaches such as the direct use of a bioactive natural product or its analogues, pharmacophore development and drug-antibody conjugates. The chemical synthesis and challenges of using natural product-based PROTACs are summarised. The review also highlights methods to detect the ternary complexes necessary for PROTAC mechanism of action.
Topics: Drug Discovery; Proteolysis Targeting Chimera; Biological Products; Proteolysis; Ligands
PubMed: 36196977
DOI: 10.1039/d2np00038e -
Medicinal Research Reviews May 2022Proteolysis targeting chimaeras (PROTACs) is a cutting edge and rapidly growing technique for new drug discovery and development. Currently, the largest challenge in the... (Review)
Review
Proteolysis targeting chimaeras (PROTACs) is a cutting edge and rapidly growing technique for new drug discovery and development. Currently, the largest challenge in the molecular design and drug development of PROTACs is efficient identification of potent and drug-like degraders. This review aims to comprehensively summarize and analyse state-of-the-art methods and strategies in the design of PROTACs. We provide a detailed illustration of the general principles and tactics for designing potent PROTACs, highlight representative case studies, and discuss the advantages and limitations of these strategies. Particularly, structure-based rational PROTAC design and emerging new types of PROTACs (e.g., homo-PROTACs, multitargeting PROTACs, photo-control PROTACs and PROTAC-based conjugates) will be focused on.
Topics: Drug Discovery; Humans; Proteolysis
PubMed: 35001407
DOI: 10.1002/med.21877 -
Nature Chemical Biology Nov 2022
Topics: Proteolysis; Proteasome Endopeptidase Complex
PubMed: 36266348
DOI: 10.1038/s41589-022-01164-7 -
Nature Chemical Biology Sep 2022
Topics: Proteolysis; Ubiquitin-Protein Ligases
PubMed: 35995863
DOI: 10.1038/s41589-022-01124-1 -
Nature Reviews. Drug Discovery Nov 2022
Topics: Humans; Drug Discovery; Intercellular Signaling Peptides and Proteins; Proteolysis
PubMed: 36171334
DOI: 10.1038/d41573-022-00159-2 -
Nature Reviews. Drug Discovery Aug 2022
Topics: Drug Discovery; Humans; Intercellular Signaling Peptides and Proteins; Proteolysis
PubMed: 35787688
DOI: 10.1038/d41573-022-00112-3 -
Trends in Pharmacological Sciences Nov 2023
Topics: Humans; Proteolysis
PubMed: 37832526
DOI: 10.1016/j.tips.2023.09.004 -
Future Medicinal Chemistry Apr 2022
Topics: Antiviral Agents; Proteolysis; Ubiquitination
PubMed: 35134309
DOI: 10.4155/fmc-2022-0005 -
Angewandte Chemie (International Ed. in... Mar 2024Many of the highest priority targets in a wide range of disease states are difficult-to-drug proteins. The development of reversible small molecule inhibitors for the... (Review)
Review
Many of the highest priority targets in a wide range of disease states are difficult-to-drug proteins. The development of reversible small molecule inhibitors for the active sites of these proteins with sufficient affinity and residence time on-target is an enormous challenge. This has engendered interest in strategies to increase the potency of a given protein inhibitor by routes other than further improvement in gross affinity. Amongst these, the development of catalytic protein inhibitors has garnered the most attention and investment, particularly with respect to protein degraders, which catalyze the destruction of the target protein. This article discusses the genesis of the burgeoning field of catalytic inhibitors, the current state of the art, and exciting future directions.
Topics: Proteins; Catalysis; Catalytic Domain; Proteolysis
PubMed: 38064411
DOI: 10.1002/anie.202316726 -
Drug Discovery Today. Technologies Apr 2019
Topics: Drug Discovery; Proteins; Proteolysis; Small Molecule Libraries; Ubiquitination
PubMed: 31200853
DOI: 10.1016/j.ddtec.2019.04.002