Approaches for the Discovery of Small Molecule Ligands Targeting microRNAs

2017 ◽  
pp. 79-110 ◽  
Author(s):  
Daniel A. Lorenz ◽  
Amanda L. Garner
Keyword(s):  
Small Molecule ◽  
Small Molecule Ligands

scholarly journals Allergens and their associated small molecule ligands ‐ their dual role in sensitization

Allergy ◽  
2021 ◽  
Author(s):  
Maksymilian Chruszcz ◽  
Fook Tim Chew ◽  
Karin Hoffmann‐Sommergruber ◽  
Barry K. Hurlburt ◽  
Geoffrey A. Mueller ◽  
...  
Keyword(s):  
Small Molecule ◽  
Dual Role ◽  
Small Molecule Ligands

Targeting FKBP isoforms with small-molecule ligands

2011 ◽  
Vol 11 (4) ◽  
pp. 365-371 ◽  
Author(s):  
Elizabeth A Blackburn ◽  
Malcolm D Walkinshaw
Keyword(s):  
Small Molecule ◽  
Small Molecule Ligands

scholarly journals Actions of the Small Molecule Ligands SW106 and AH-3960 on the Type-1 Parathyroid Hormone Receptor

2015 ◽  
Vol 29 (2) ◽  
pp. 307-321 ◽  
Author(s):  
Percy H. Carter ◽  
Thomas Dean ◽  
Brijesh Bhayana ◽  
Ashok Khatri ◽  
Raj Rajur ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Small Molecule ◽  
Hormone Receptor ◽  
Transmembrane Domain ◽  
Receptor Activation ◽  
Blood Calcium ◽  
Parathyroid Hormone Receptor ◽  
Peptide Analog ◽  
Amino Terminal ◽  
Small Molecule Ligands

Abstract The parathyroid hormone receptor-1 (PTHR1) plays critical roles in regulating blood calcium levels and bone metabolism and is thus of interest for small-molecule ligand development. Of the few small-molecule ligands reported for the PTHR1, most are of low affinity, and none has a well-defined mechanism of action. Here, we show that SW106 and AH-3960, compounds previously identified to act as an antagonist and agonist, respectively, on the PTHR1, each bind to PTHR1-delNT, a PTHR1 construct that lacks the large amino-terminal extracellular domain used for binding endogenous PTH peptide ligands, with the same micromolar affinity with which it binds to the intact PTHR1. SW106 antagonized PTHR1-mediated cAMP signaling induced by the peptide analog, M-PTH(1–11), as well as by the native PTH(1–9) sequence, as tethered to the extracellular end of transmembrane domain (TMD) helix-1 of the receptor. SW106, however, did not function as an inverse agonist on either PTHR1-H223R or PTHR1-T410P, which have activating mutations at the cytoplasmic ends of TMD helices 2 and 6, respectively. The overall data indicate that SW106 and AH-3960 each bind to the PTHR1 TMD region and likely to within an extracellularly exposed area that is occupied by the N-terminal residues of PTH peptides. Additionally, they suggest that the inhibitory effects of SW106 are limited to the extracellular portions of the TMD region that mediate interactions with agonist ligands but do not extend to receptor-activation determinants situated more deeply in the helical bundle. The study helps to elucidate potential mechanisms of small-molecule binding at the PTHR1.

Supramolecular Host-Guest Inclusion for Distinguishing Cucurbit[7]uril-Based Pseudorotaxanes from Small-Molecule Ligands in Coordination Assembly with a Uranyl Center

2017 ◽  
Vol 23 (56) ◽  
pp. 13995-14003 ◽  
Author(s):  
Lei Mei ◽  
Zhen-Ni Xie ◽  
Kong-qiu Hu ◽  
Li-Yong Yuan ◽  
Zeng-Qiang Gao ◽  
...  
Keyword(s):  
Small Molecule ◽  
Small Molecule Ligands

scholarly journals High-Throughput Implementation of the NanoBRET Target Engagement Intracellular Kinase Assay to Reveal Differential Compound Engagement by SIK2/3 Isoforms

2019 ◽  
Vol 25 (2) ◽  
pp. 215-222
Author(s):  
Hyun Yong Jin ◽  
Yanyan Tudor ◽  
Kaylee Choi ◽  
Zhifei Shao ◽  
Brian A. Sparling ◽  
...  
Keyword(s):  
Small Molecule ◽  
High Throughput ◽  
High Throughput Screening ◽  
Inflammatory Responses ◽  
Therapeutic Benefit ◽  
Kinase Assay ◽  
Target Engagement ◽  
Biologically Relevant ◽  
Safety Margins ◽  
Small Molecule Ligands

The real-time quantification of target engagement (TE) by small-molecule ligands in living cells remains technically challenging. Systematic quantification of such interactions in a high-throughput setting holds promise for identification of target-specific, potent small molecules within a pathophysiological and biologically relevant cellular context. The salt-inducible kinases (SIKs) belong to a subfamily of the AMP-activated protein kinase (AMPK) family and are composed of three isoforms in humans (SIK1, SIK2, and SIK3). They modulate the production of pro- and anti-inflammatory cytokines in immune cells. Although pan-SIK inhibitors are sufficient to reverse SIK-dependent inflammatory responses, the apparent toxicity associated with SIK3 inhibition suggests that isoform-specific inhibition is required to realize therapeutic benefit with acceptable safety margins. Here, we used the NanoBRET TE intracellular kinase assay, a sensitive energy transfer technique, to directly measure molecular proximity and quantify TE in HEK293T cells overexpressing SIK2 or SIK3. Our 384-well high-throughput screening of 530 compounds demonstrates that the NanoBRET TE intracellular kinase assay was sensitive and robust enough to reveal differential engagement of candidate compounds with the two SIK isoforms and further highlights the feasibility of high-throughput implementation of NanoBRET TE intracellular kinase assays for target-driven small-molecule screening.

scholarly journals Small-Molecule Ligands of Methyl-Lysine Binding Proteins

2011 ◽  
Vol 54 (7) ◽  
pp. 2504-2511 ◽  
Author(s):  
J. Martin Herold ◽  
Tim J. Wigle ◽  
Jacqueline L. Norris ◽  
Robert Lam ◽  
Victoria K. Korboukh ◽  
...  
Keyword(s):  
Small Molecule ◽  
Binding Proteins ◽  
Small Molecule Ligands

scholarly journals Ligands with poly-fluorophenyl moieties promote a local structural rearrangement in the Spinach2 and Broccoli aptamers that increases ligand affinities

2021 ◽  
Author(s):  
Sharif Anisuzzaman ◽  
Ivan M Geraskin ◽  
Muslum Ilgu ◽  
Lee Bendickson ◽  
George A Kraus ◽  
...  
Keyword(s):  
Nucleic Acids ◽  
Ligand Binding ◽  
Small Molecule ◽  
Binding Pocket ◽  
Structural Rearrangement ◽  
Structural Reorganization ◽  
Ligand Binding Pocket ◽  
Rna Remodeling ◽  
Small Molecule Ligands ◽  
Target Molecules

The interaction of nucleic acids with their molecular targets often involves structural reorganization that may traverse a complex folding landscape. With the more recent recognition that many RNAs, both coding and noncoding, may regulate cellular activities by interacting with target molecules, it becomes increasingly important to understand the means by which nucleic acids interact with their targets and how drugs might be developed that can influence critical folding transitions. We have extensively investigated the interaction of the Spinach2 and Broccoli aptamers with a library of small molecule ligands modified by various extensions from the imido nitrogen of DFHBI (3,5-difluoro-4-hydroxybenzylidene imidazolinone) that reach out from the Spinach2 ligand binding pocket. Studies of the interaction of these compounds with the aptamers revealed that poly-fluorophenyl-modified ligands initiate a slow change in aptamer affinity that takes an extended time (half-life of ~40 min) to achieve. The change in affinity appears to involve an initial disruption of the entrance to the ligand binding pocket followed by a gradual lockdown for which the most likely driving force is an interaction of the gateway adenine with a nearby 2'OH group. These results suggest that poly-fluorophenyl modifications might increase the ability of small molecule drugs to disrupt local structure and promote RNA remodeling.

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