Functionalized Congeners of 2H-Chromene P2Y6 Receptor Antagonists DOI Creative Commons
Paola Oliva,

Asmita Pramanik,

Kwan‐Young Jung

et al.

Cells, Journal Year: 2024, Volume and Issue: 13(16), P. 1366 - 1366

Published: Aug. 16, 2024

The P2Y6 receptor (P2Y6R), a Gq-coupled receptor, is potential drug discovery target for various inflammatory and degenerative conditions. Antagonists have been shown to attenuate colitis, acute lung injury, etc. In the search competitive antagonists, we investigated SAR of 3-nitro-2-(trifluoromethyl)-2H-chromene derivatives, although high affinity lacking. We now reveal that long-chain amino-functionalized congeners display greatly enhanced in antagonism UDP-induced Ca2+ mobilization human (h) P2Y6R-transfected 1321N1 astrocytoma cells. A 6-(Boc-amino-n-heptylethynyl) analogue 30 (MRS4940) had an IC50 162 nM, which was 123-fold greater than corresponding unprotected primary alkylamine, 107-fold pivaloyl derivative 30, 132-fold selective compared P2Y14R. However, similar Boc-amino chains attached at 8-position produced weak µM affinity. Thus, P2Y6R depended on chain length, attachment point, terminal functionality. Off-target activities, 45 sites, were tested acylamino derivatives 20, 24, 26, 31, 37, showed multiple interactions, particularly biogenic amine receptors. more potent analogues may be suitable evaluation inflammation cancer models, will performed future studies.

Language: Английский

Lipid Trolling to Optimize A3 Adenosine Receptor-Positive Allosteric Modulators (PAMs) DOI
Balaram Pradhan, Matteo Pavan, Courtney Fisher

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(14), P. 12221 - 12247

Published: July 3, 2024

A

Language: Английский

Citations

5
Thermal Titration Molecular Dynamics: The Revenge of the Fragments DOI Creative Commons
Matteo Pavan, Silvia Menin, Andrea Dodaro

et al.

Journal of Chemical Information and Modeling, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 21, 2025

During the last 20 years, fragment-based drug discovery approach gained popularity in both industrial and academic settings due to its efficient exploration of chemical space. This bottom-up relies on identifying high-efficiency small ligands (fragments) that bind a target binding site then rationally evolve them into mature druglike compounds. To achieve such task, researchers rely accurate information about ligand mode, usually obtained through experimental techniques, as X-ray crystallography or computer simulations. However, physicochemical characteristics fragments limit accuracy reliability computational predictions their mode. article presents new Thermal Titration Molecular Dynamics (TTMD) protocol, recently developed enhanced sampling method for qualitatively estimating protein-ligand-binding stability, specifically tuned refinement fragment docking results. The protocol has been applied eight pharmaceutically relevant targets 12 different test cases, including with very low molecular weight structural complexity (MiniFrag/FragLites). In more than 80% TTMD successfully identified native mode among set poses, outperforming alone proving be useful tool assist screening optimization process.

Language: Английский

Citations

0
E. B. Hershberg Award: Taming Inflammation by Tuning Purinergic Signaling DOI
Kenneth A. Jacobson

Accounts of Chemical Research, Journal Year: 2025, Volume and Issue: unknown

Published: March 5, 2025

ConspectusThe author presents his personal story from early contributions in purinergic receptor research to present-day structure-guided medicinal chemistry. Modulating signaling (encompassing pyrimidine nucleotides as well) and other nucleoside targets with small molecules is fruitful for identifying new directions therapeutic intervention. Purinergic encompasses four adenosine receptors, eight P2Y receptors that respond various extracellular nucleotides, trimeric P2X mainly ATP. Each organ tissue the body expresses some combination of this family cell-surface along enzymes transporters form, degrade, process native nucleotide agonists. The system responds physiological stress an organ, example by increasing energy supply or decreasing demand. are widespread on immune cells, such activation boosts response when where it needed, repel infection. In contrast, which activated later process─as stress-elevated ATP hydrolyzed locally ectonucleotidases─tend put brakes inflammation can be used correct imbalance pro- versus anti-inflammatory signals, chronic pain. Hypoxia activates immunosuppressive adenosine-A2A axis, originally formulated Sitkovsky, suppresses tumor microenvironment make a cancer more aggressive. Conversely, effects agonists have numerous applications. Modulators also show promise treating pain, metabolic disorders, inflammation. Thus, control harnessed wide range conditions, neurodegeneration autoimmune inflammatory diseases ischemia brain heart.The author's receiving American Chemical Society's top award chemistry 2023 provides opportunity summarize these developments their origins empirical probing receptor-ligand structure-activity relationship (SAR) current structure-based approaches, including conformational selectivity toward signaling. work each target began either before soon after was cloned, initial focus academic exercise use organic develop SAR target. Jacobson lab has introduced chemical probes 17 well associated regulators. Furthermore, surprisingly, conformationally constrained analogues designed inhibit non-purinergic selectively, opioid serotonin monoamine transporters. Only did applications pharmacological become apparent. largely enabled biological making definitive tool compounds available. Five laboratory (four derivatives) currently clinical trials (autoimmune liver conditions) acute (stroke, traumatic injury) conditions.

Language: Английский

Citations

0
Biased signaling in GPCRs: Structural insights and implications for drug development DOI Creative Commons

Yuanyuan Ma,

Brandon Patterson, Lan Zhu

et al.

Pharmacology & Therapeutics, Journal Year: 2024, Volume and Issue: unknown, P. 108786 - 108786

Published: Dec. 1, 2024

Language: Английский

Citations

1
Functionalized Congeners of 2H-Chromene P2Y6 Receptor Antagonists DOI Creative Commons
Paola Oliva,

Asmita Pramanik,

Kwan‐Young Jung

et al.

Cells, Journal Year: 2024, Volume and Issue: 13(16), P. 1366 - 1366

Published: Aug. 16, 2024

The P2Y6 receptor (P2Y6R), a Gq-coupled receptor, is potential drug discovery target for various inflammatory and degenerative conditions. Antagonists have been shown to attenuate colitis, acute lung injury, etc. In the search competitive antagonists, we investigated SAR of 3-nitro-2-(trifluoromethyl)-2H-chromene derivatives, although high affinity lacking. We now reveal that long-chain amino-functionalized congeners display greatly enhanced in antagonism UDP-induced Ca2+ mobilization human (h) P2Y6R-transfected 1321N1 astrocytoma cells. A 6-(Boc-amino-n-heptylethynyl) analogue 30 (MRS4940) had an IC50 162 nM, which was 123-fold greater than corresponding unprotected primary alkylamine, 107-fold pivaloyl derivative 30, 132-fold selective compared P2Y14R. However, similar Boc-amino chains attached at 8-position produced weak µM affinity. Thus, P2Y6R depended on chain length, attachment point, terminal functionality. Off-target activities, 45 sites, were tested acylamino derivatives 20, 24, 26, 31, 37, showed multiple interactions, particularly biogenic amine receptors. more potent analogues may be suitable evaluation inflammation cancer models, will performed future studies.

Language: Английский

Citations

0