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Protein and Protein Structure02:15

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Proteins are one of the most abundant organic molecules in living systems and have the most diverse range of functions of all macromolecules. Proteins may be structural, regulatory, contractile, or protective. They may serve in transport, storage, or membranes; or they may be toxins or enzymes. Their structures, like their functions, vary greatly. They are all, however, amino acid polymers arranged in a linear sequence.
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Structural proteins are a category of proteins responsible for functions ranging from cell shape and movement to providing support to major structures such as bones, cartilage, hair, and muscles. This group includes proteins such as collagen, actin, myosin, and keratin.
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ER is the primary site for the maturation and folding of soluble and transmembrane secretory proteins. The calnexin cycle is a specific chaperone system that folds and assesses the confirmation of N-glycosylated proteins before they can exit the ER lumen. The primary players of this quality check pipeline are the lectins, ER-resident chaperones, and a glucosyl transferase enzyme. In case the calnexin system in the lumen fails to salvage a misfolded protein, it is transported to the cytoplasm...
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Three main types of fibers are secreted by fibroblasts: collagen fibers, elastic fibers, and reticular fibers. Collagen fiber is made from fibrous protein subunits linked together to form a long, straight fiber. Collagen fibers, while flexible, have great tensile strength, resist stretching, and give ligaments and tendons their characteristic resilience and strength. These fibers hold connective tissues together, even during the body's movement.
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Updated: Feb 15, 2026

Rapid Assessment of Membrane Protein Quality by Fluorescent Size Exclusion Chromatography
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Bioisosteric Replacements Extracted from High-Quality Structures in the Protein Databank.

Matthew P Seddon1, David A Cosgrove2,3, Valerie J Gillet1

  • 1Information School, The University of Sheffield, Regent Court, 211 Portobello, Sheffield, S1 4DP, UK.

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|January 10, 2018
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Summary

This study analyzes bioisosteric fragments in drug discovery, identifying similar molecular fragments across 121 protein targets to aid lead optimization. Findings reveal common bioisosteric pairs, offering insights for designing improved drug candidates.

Keywords:
PDBbioisosteresfragmentationmolecular overlaypharmacophores

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Area of Science:

  • Medicinal Chemistry
  • Computational Drug Discovery
  • Structural Biology

Background:

  • Bioisosterism is crucial for lead optimization in drug discovery, aiming to enhance molecular properties while preserving others.
  • Analyzing bioisosteric fragments helps understand structure-activity relationships and guide the design of novel therapeutics.
  • Established datasets of ligands and protein targets provide a foundation for systematic bioisosterism studies.

Purpose of the Study:

  • To analyze bioisosteric fragments within ligands across a diverse set of 121 protein targets.
  • To investigate the occurrence and generality of bioisosteric fragment pairs in protein binding sites.
  • To assess the cross-target commonality of identified bioisosteric relationships.

Main Methods:

  • Ligands from a dataset of 121 protein targets were analyzed.
  • The BRICS fragmentation scheme was employed to break down ligands into constituent fragments.
  • Pairwise analysis identified fragments occupying similar volumes within protein binding sites as bioisosteric.
  • Two levels of generality were considered: fragment volume similarity and similarity with identical attachment points.

Main Results:

  • Bioisosteric fragment pairs were identified across multiple protein targets.
  • The study explored variations in bioisosteric fragment identification based on attachment point considerations.
  • Analysis indicated the extent to which identified bioisosteric pairs are conserved across different protein targets.

Conclusions:

  • Bioisosteric fragment analysis provides valuable insights for drug lead optimization.
  • Understanding fragment commonality across targets can inform broader drug design strategies.
  • The methodology offers a systematic approach to exploring bioisosterism in medicinal chemistry.