Druggable Allosteric Sites in β‐Propeller Lectins

Shanina, Elena; Kuhaudomlarp, Sakonwan; Lal, Kanhaya; Seeberger, Peter H.; Rademacher, Christoph

doi:10.1002/anie.202109339

Cited by 12 publications

(6 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indeed, the competitors displaced 61 in LecA, LecB and DC-SIGN. On the other hand, the 19 F peak intensities remained unchanged in Langerin and BambL, which was probably due to 61 binding to the secondary druggable sites 58 – 60 . Cumulatively, our results proposed that malonates interact with the orthosteric sites of metal-dependent lectins LecA, LecB and DC-SIGN in a Ca 2+ -dependent manner.…”

Section: Resultsmentioning

confidence: 97%

Targeting undruggable carbohydrate recognition sites through focused fragment library design

et al. 2022

Self Cite

View full text Add to dashboard Cite

Carbohydrate-protein interactions are key for cell-cell and host-pathogen recognition and thus, emerged as viable therapeutic targets. However, their hydrophilic nature poses major limitations to the conventional development of drug-like inhibitors. To address this shortcoming, four fragment libraries were screened to identify metal-binding pharmacophores (MBPs) as novel scaffolds for inhibition of Ca2+-dependent carbohydrate-protein interactions. Here, we show the effect of MBPs on the clinically relevant lectins DC-SIGN, Langerin, LecA and LecB. Detailed structural and biochemical investigations revealed the specificity of MBPs for different Ca2+-dependent lectins. Exploring the structure-activity relationships of several fragments uncovered the functional groups in the MBPs suitable for modification to further improve lectin binding and selectivity. Selected inhibitors bound efficiently to DC-SIGN-expressing cells. Altogether, the discovery of MBPs as a promising class of Ca2+-dependent lectin inhibitors creates a foundation for fragment-based ligand design for future drug discovery campaigns.

show abstract

Section: Resultsmentioning

confidence: 97%

Targeting undruggable carbohydrate recognition sites through focused fragment library design

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…These methods rely on analyzing the energetics of interactions between the protein and ligand. SiteMap and SITEHOUND are two such methods that use a single probe, typically a methane or water molecule, to evaluate the binding affinity of small molecules to proteins (Adeniji et al, 2019; Shanina et al, 2022). The SiteMap method has been particularly successful in discovering allosteric sites, such as the “tunnel” site, “latching” site, and “groove” site, which have been identified on SHP2 (Halgren, 2009; Hernandez et al, 2009).…”

Section: Methodsmentioning

confidence: 99%

Allosteric modulation of SHP2: Quest from known to unknown

Wang

Zhu

et al. 2023

Drug Development Research

View full text Add to dashboard Cite

Src homology‐2 domain‐containing protein tyrosine phosphatase‐2 (SHP2) is a key regulatory factor in the cell cycle and its activating mutations play an important role in the development of various cancers, making it an important target for antitumor drugs. Due to the highly conserved amino acid sequence and positively charged nature of the active site of SHP2, it is difficult to discover inhibitors with high affinity for the catalytic site of SHP2 and sufficient cell permeability, making it considered an “undruggable” target. However, the discovery of allosteric regulation mechanisms provides new opportunities for transforming undruggable targets into druggable ones. Given the limitations of orthosteric inhibitors, SHP2 allosteric inhibitors have become a more selective and safer research direction. In this review, we elucidate the oncogenic mechanism of SHP2 and summarize the discovery methods of SHP2 allosteric inhibitors, providing new strategies for the design and improvement of SHP2 allosteric inhibitors.

show abstract

“…PRE NMR experiments can thus be used to obtain important information about recognition processes in solution, and with the advent of AlphaFold future PRE-based studies would have access to a structural model for the interpretation of experimental NMR data. Unraveling and delineating dynamic communication networks of key allosteric interactions can be aided by NMR experiments , and cooperatively controlled processes in which each binding step is under control of a previous binding event have been described, as well as allosteric regulation of lysosomal enzyme recognition and druggable allosteric sites in lectins. , The subtle interaction processes, which may be unveiled to some extent by NMR spectroscopy experiments, should be possible to fully understand in the future when experimental data are combined with artificial intelligence methodology.…”

Section: Outlook and Summarymentioning

confidence: 99%

Glycan Shape, Motions, and Interactions Explored by NMR Spectroscopy

Widmalm

2024

JACS Au

View full text Add to dashboard Cite

Glycans in the form of oligosaccharides, polysaccharides, and glycoconjugates are ubiquitous in nature, and their structures range from linear assemblies to highly branched and decorated constructs. Solution state NMR spectroscopy facilitates elucidation of preferred conformations and shapes of the saccharides, motions, and dynamic aspects related to processes over time as well as the study of transient interactions with proteins. Identification of intermolecular networks at the atomic level of detail in recognition events by carbohydrate-binding proteins known as lectins, unraveling interactions with antibodies, and revealing substrate scope and action of glycosyl transferases employed for synthesis of oligo-and polysaccharides may efficiently be analyzed by NMR spectroscopy. By utilizing NMR active nuclei present in glycans and derivatives thereof, including isotopically enriched compounds, highly detailed information can be obtained by the experiments. Subsequent analysis may be aided by quantum chemical calculations of NMR parameters, machine learning-based methodologies and artificial intelligence. Interpretation of the results from NMR experiments can be complemented by extensive molecular dynamics simulations to obtain three-dimensional dynamic models, thereby clarifying molecular recognition processes involving the glycans.

show abstract

Druggable Allosteric Sites in β‐Propeller Lectins

Cited by 12 publications

References 43 publications

Targeting undruggable carbohydrate recognition sites through focused fragment library design

Targeting undruggable carbohydrate recognition sites through focused fragment library design

Allosteric modulation of SHP2: Quest from known to unknown

Glycan Shape, Motions, and Interactions Explored by NMR Spectroscopy

Contact Info

Product

Resources

About