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Journal of Chemical Information and... Oct 2011We describe a graphical system for automatically generating multiple 2D diagrams of ligand-protein interactions from 3D coordinates. The diagrams portray the...
We describe a graphical system for automatically generating multiple 2D diagrams of ligand-protein interactions from 3D coordinates. The diagrams portray the hydrogen-bond interaction patterns and hydrophobic contacts between the ligand(s) and the main-chain or side-chain elements of the protein. The system is able to plot, in the same orientation, related sets of ligand-protein interactions. This facilitates popular research tasks, such as analyzing a series of small molecules binding to the same protein target, a single ligand binding to homologous proteins, or the completely general case where both protein and ligand change.
Topics: Amino Acid Sequence; Binding Sites; Databases, Protein; Drug Discovery; Humans; Ligands; Models, Molecular; Molecular Sequence Data; Protein Binding; Protein Conformation; Proteins; Sequence Homology, Amino Acid; Software
PubMed: 21919503
DOI: 10.1021/ci200227u -
Chemical Society Reviews May 2022In recent years, proteolysis-targeting chimeras (PROTACs), capable of achieving targeted protein degradation, have proven their great therapeutic potential and... (Review)
Review
In recent years, proteolysis-targeting chimeras (PROTACs), capable of achieving targeted protein degradation, have proven their great therapeutic potential and usefulness as molecular biology tools. These heterobifunctional compounds are comprised of a protein-targeting ligand, an appropriate linker, and a ligand binding to the E3 ligase of choice. A successful PROTAC induces the formation of a ternary complex, leading to the E3 ligase-mediated ubiquitination of the targeted protein and its proteasomal degradation. In over 20 years since the concept was first demonstrated, the field has grown substantially, mainly due to the advancements in the discovery of non-peptidic E3 ligase ligands. Development of small-molecule E3 binders with favourable physicochemical profiles aided the design of PROTACs, which are known for breaking the rules of established guidelines for discovering small molecules. Synthetic accessibility of the ligands and numerous successful applications led to the prevalent use of cereblon and von Hippel-Lindau as the hijacked E3 ligase. However, the pool of over 600 human E3 ligases is full of untapped potential, which is why expanding the artillery of E3 ligands could contribute to broadening the scope of targeted protein degradation. In this comprehensive review, we focus on the chemistry aspect of the PROTAC design process by providing an overview of liganded E3 ligases, their chemistries, appropriate derivatisation, and synthetic approaches towards their incorporation into heterobifunctional degraders. By covering syntheses of both established and underexploited E3 ligases, this review can serve as a chemistry blueprint for PROTAC researchers during their future ventures into the complex field of targeted protein degradation.
Topics: Humans; Ligands; Proteolysis; Ubiquitin-Protein Ligases; Ubiquitination
PubMed: 35393989
DOI: 10.1039/d2cs00148a -
Small (Weinheim An Der Bergstrasse,... Jul 2021The design of surface ligands is crucial for ligand-protected gold nanoclusters (Au NCs). Besides providing good protection for Au NCs, the surface ligands also play the... (Review)
Review
The design of surface ligands is crucial for ligand-protected gold nanoclusters (Au NCs). Besides providing good protection for Au NCs, the surface ligands also play the following two important roles: i) as the outermost layer of Au NCs, the ligands will directly interact with the exterior environment (e.g., solvents, molecules and cells) influencing Au NCs in various applications; and ii) the interfacial chemistry between ligands and gold atoms can determine the structures, as well as the physical and chemical properties of Au NCs. A delicate ligand design in Au NCs (or other metal NCs) needs to consider the covalent bonds between ligands and gold atoms (e.g., gold-sulfur (Au-S) and gold-phosphorus (Au-P) bond), the physics forces between ligands (e.g., hydrophobic and van der Waals forces), and the ionic forces between the functional groups of ligands (e.g., carboxylic (COOH) and amine group (NH )); which form the underlying chemistry and discussion focus of this review article. Here, detailed discussions on the effects of surface ligands (e.g., thiolate, phosphine, and alkynyl ligands; or hydrophobic and hydrophilic ligands) on the synthesis, structures, and properties of Au NCs; highlighting the design principles in the surface engineering of Au NCs for diverse emerging applications, are provided.
Topics: Gold; Ligands; Metal Nanoparticles
PubMed: 33511773
DOI: 10.1002/smll.202004381 -
Journal of Controlled Release :... Dec 2021Ligands, mostly binding to proteins to form complexes and catalyze chemical reactions, can serve as drug and probe molecules, as well as sensing elements. DNA... (Review)
Review
Ligands, mostly binding to proteins to form complexes and catalyze chemical reactions, can serve as drug and probe molecules, as well as sensing elements. DNA nanotechnology can integrate the high editability of DNA nanostructures and the biological activity of ligands into functionalized DNA nanostructures in a manner of controlled ligand stoichiometry, type, and arrangement, which provides significant advantages for targeted therapeutics and diagnostics. As therapeutic agents, multiple- and multivalent-ligands functionalized DNA nanostructures increase ligand-receptor affinity and activate multivalent ligand-receptor interactions, enabling improved regulation of cell signaling and enhanced control of cell behavior. As diagnostic agents, multiple ligands interaction via DNA nanostructures endows DNA nanosensors with high sensitivity and excellent signal transduction capability. Herein, we review the principles and advantages of using DNA nanostructures to manipulate ligands for targeted therapeutics and diagnostics and provide future perspectives.
Topics: Catalysis; DNA; Ligands; Nanostructures; Nanotechnology
PubMed: 34748871
DOI: 10.1016/j.jconrel.2021.11.004 -
Journal of Chromatography. A Aug 2022Chiral ligand exchange capillary electrophoresis (CLE-CE) has become an area of tremendous interest in chiral separation science, particularly in life science and... (Review)
Review
Chiral ligand exchange capillary electrophoresis (CLE-CE) has become an area of tremendous interest in chiral separation science, particularly in life science and pharmaceutical, due to its notable simplicity, tunable migration order, and outstanding performance. This approach effectively separates enantiomers in drugs, food products and bio-samples. Nevertheless, the main challenges in CLE-CE are the limited chiral ligand-species, unclear mechanism of thermodynamic enantioseparation and unsatisfactory enantioseparation efficiency, which restrict its applications. Designing desirable chiral ligand-species and exploring profitable central metal ions are considered to be efficient strategies for addressing these obstacles, which can improve the performance of CLE-CE and expand its application in living bio-systems. This review introduces the concept of desirable chiral ligand species and highlights the latest CLE-CE research in the last decade, with special emphasis on boosting its enantioseparation efficiency and expanding its cutting-edge application. Moreover, further research in the CLE-CE field is prospected.
Topics: Electrophoresis, Capillary; Ligands; Stereoisomerism
PubMed: 35952411
DOI: 10.1016/j.chroma.2022.463381 -
Nature Methods Apr 2024
Topics: Ligands
PubMed: 38609557
DOI: 10.1038/s41592-024-02249-y -
ACS Sensors Dec 2020The last two decades have seen great advancements in fundamental understanding and applications of metallic nanoparticles stabilized by mixed-ligand monolayers.... (Review)
Review
The last two decades have seen great advancements in fundamental understanding and applications of metallic nanoparticles stabilized by mixed-ligand monolayers. Identifying and controlling the organization of multiple ligands in the nanoparticle monolayer has been studied, and its effect on particle properties has been examined. Mixed-ligand protected particles have shown advantages over monoligand protected particles in fields such as catalysis, self-assembly, imaging, and drug delivery. In this Review, the use of mixed-ligand monolayer protected nanoparticles for sensing applications will be examined. This is the first time this subject is examined as a whole. Mixed-ligand nanoparticle-based sensors are revealed to be divided into four groups, each of which will be discussed. The first group consists of ligands that work cooperatively to improve the sensors' properties. In the second group, multiple ligands are utilized for sensing multiple analytes. The third group combines ligands used for analyte recognition and signal production. In the final group, a sensitive, but unstable, functional ligand is combined with a stabilizing ligand. The Review will conclude by discussing future challenges and potential research directions for this promising subject.
Topics: Catalysis; Ligands; Metal Nanoparticles
PubMed: 33241680
DOI: 10.1021/acssensors.0c02124 -
Nature Chemical Biology Nov 2023With an eye toward expanding chemistries used for covalent ligand discovery, we elaborated an umpolung strategy that exploits the 'polarity reversal' of sulfur when...
With an eye toward expanding chemistries used for covalent ligand discovery, we elaborated an umpolung strategy that exploits the 'polarity reversal' of sulfur when cysteine is oxidized to sulfenic acid, a widespread post-translational modification, for selective bioconjugation with C-nucleophiles. Here we present a global map of a human sulfenome that is susceptible to covalent modification by members of a nucleophilic fragment library. More than 500 liganded sulfenic acids were identified on proteins across diverse functional classes, and, of these, more than 80% were not targeted by electrophilic fragment analogs. We further show that members of our nucleophilic fragment library can impair functional protein-protein interactions involved in nuclear oncoprotein transport and DNA damage repair. Our findings reveal a vast expanse of ligandable sulfenic acids in the human proteome and highlight the utility of nucleophilic small molecules in the fragment-based covalent ligand discovery pipeline, presaging further opportunities using non-traditional chemistries for targeting proteins.
Topics: Humans; Cysteine; Ligands; Sulfenic Acids; Proteome; Protein Processing, Post-Translational
PubMed: 37248412
DOI: 10.1038/s41589-023-01330-5 -
Journal of Biomolecular Structure &... Mar 2023The three subtypes of estrogen-related receptors ERR, ERR, and ERR are nuclear receptors mediating metabolic processes in various tissues such as the skeletal muscle,...
The three subtypes of estrogen-related receptors ERR, ERR, and ERR are nuclear receptors mediating metabolic processes in various tissues such as the skeletal muscle, fat tissue, bone, and liver. Although the knowledge on their physiological ligands is limited, they have been implicated as drug targets for important indications including diabetes, cardiovascular diseases, and osteoporosis. As in other nuclear receptors, their ligand binding pocket is buried within the core of the receptor and connected to its surrounding by ligand pathways. Here, we investigated these pathways with conventional molecular dynamics as well as metadynamics simulations to reveal their distribution and their capability to facilitate ligand translocation. Dependent on the ERR subtype and the conformational state of the receptor, we could detect different pathways to be favored. Overall, the results suggested pathways IIIa and IIIb to be favored in the agonistic conformation, while antagonists preferred pathways I, II, and V. Along the pathways, the ligands passed different gating mechanisms of the receptor, including groups of protein residues as well as whole secondary structure elements, to leave the binding site. Even though these pathways are suggested to influence ligand specificity of the receptors and their elucidation might advance rational drug design, they have not yet been studied in ERRs.Communicated by Ramaswamy H. Sarma.
Topics: Ligands; Molecular Conformation; Binding Sites; Estrogens
PubMed: 35068382
DOI: 10.1080/07391102.2022.2027818 -
BioEssays : News and Reviews in... Aug 2000Nuclear receptors form a superfamily of ligand-activated transcription factors that regulate various physiological functions, from development to homeostasis, in... (Review)
Review
Nuclear receptors form a superfamily of ligand-activated transcription factors that regulate various physiological functions, from development to homeostasis, in metazoans. The superfamily contains not only receptors for known ligands but also a large number of so-called orphan receptors for which ligands do not exist or have not been identified. The evolution of ligand-binding capacity of nuclear receptors may involve either secondary loss in orphan receptors, or evolutionary acquisition of ligand-binding capacity in liganded receptors. In this review, we present arguments from phylogenetic, functional and structural studies that support the hypothesis that there have been several independent gains of ligand-binding ability of nuclear receptors during metazoan evolution.
Topics: Animals; Biological Evolution; Humans; Ligands; Models, Biological; Phylogeny; Receptors, Cytoplasmic and Nuclear
PubMed: 10918302
DOI: 10.1002/1521-1878(200008)22:8<717::AID-BIES5>3.0.CO;2-I