A Novel Somatostatin Mimic with Broad Somatotropin Release Inhibitory Factor Receptor Binding and Superior Therapeutic Potential

A gamma-pyrone derivative, comenic acid, activates the opioid-like receptor-mediated signaling pathway that modulates the NaV1.8 channels in the primary sensory neuron membrane. These channels are responsible for generation of the nociceptive signal; gamma-pyrones can therefore have a great therapeutic potential as analgesics, and this effect deserves a deeper understanding. The novelty of our approach to the design of a medicinal substance is based on a combination of the data obtained on living neurons using very sensitive physiological methods and the results of quantum-chemical calculations. This approach allows to correlate the molecular structure of gamma-pyrones with their ability to evoke a physiological response of the neuron. Comenic acid can bind two calcium cations. One of them is chelated by the carbonyl and the hydroxyl functional groups, while another one forms the salt bond with the carboxylate anion. Calcium-bound gamma-pyrones are fundamentally different in electrostatic properties from the free gamma-pyrone molecules. These two calcium ions are the key elements involved in ligand-receptor binding. It is very likely ion-ionic interactions between these cations and anionic functional groups of the opioid-like receptor that activate the latter. The calculated intercationic distance of 9.5 Å is a structural criterion for effective ligand-receptor binding of calcium-bound gamma-pyrones.

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Crystallographic and Receptor Binding Characterization of Plasmodium falciparum Macrophage Migration Inhibitory Factor Complexed to Two Potent Inhibitors

Journal of Medicinal Chemistry ◽

10.1021/jm501168q ◽

2014 ◽

Vol 57 (20) ◽

pp. 8652-8656 ◽

Cited By ~ 11

Author(s):

Georgios Pantouris ◽

Deepa Rajasekaran ◽

Alvaro Baeza Garcia ◽

Victor G. Ruiz ◽

Lin Leng ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Receptor Binding ◽

Migration Inhibitory Factor ◽

Macrophage Migration Inhibitory Factor ◽

Inhibitory Factor ◽

Macrophage Migration

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Inhibition of Macrophage Migration Inhibitory Factor Protects against Inflammation and Matrix Deposition in Kidney Tissues after Injury

Mediators of Inflammation ◽

10.1155/2016/2174682 ◽

2016 ◽

Vol 2016 ◽

pp. 1-12 ◽

Cited By ~ 9

Author(s):

Hong Lu ◽

Yongyu Bai ◽

Lianfeng Wu ◽

Weilong Hong ◽

Yong Liang ◽

...

Keyword(s):

Migration Inhibitory Factor ◽

Macrophage Migration Inhibitory Factor ◽

Therapeutic Potential ◽

Kidney Diseases ◽

Ischemia Reperfusion ◽

Specific Inhibitor ◽

Inhibitory Factor ◽

Macrophage Migration ◽

Related Factors ◽

Matrix Deposition

Background. Macrophage migration inhibitory factor (MIF) is an important immunoregulatory cytokine involved in inflammation, which may be one important reason resulting in matrix deposition in renal tissues after injury. However, the underlying mechanisms have not yet been elucidated.Methods and Results. We uncovered a crucial role of MIF in inflammation and collagen depositionin vivoandin vitro. In rats, ureteral obstruction induced tubular injury, matrix accumulation, and inflammatory cell infiltration. Additionally, enhanced MIF levels in the obstructed kidneys were closely related to the increasing numbers of CD68-positive macrophages. These obstruction-induced injuries can be relieved by recanalization, consequently resulting in downregulated expression of MIF and its receptor CD74. Similarly, ischemia reperfusion induced renal injury, and it was accompanied by elevated MIF levels and macrophages infiltration. In cultured tubular epithelial cells (TECs), aristolochic acid (AA) promoted matrix production and increased MIF expression, as well as the release of macrophage-related factors. Inhibition of MIF with an antagonist ISO-1 resulted in the abolishment of these genotypes in AA-treated TECs.Conclusion. MIF plays an important role in macrophage-related inflammation and matrix deposition in kidney tissues following injury. MIF as a specific inhibitor may have therapeutic potential for patients with inflammatory and fibrotic kidney diseases.

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Inter-Species Chimeras of Leukemia Inhibitory Factor Define a Human Receptor Binding Sitea

Annals of the New York Academy of Sciences ◽

10.1111/j.1749-6632.1995.tb32324.x ◽

2006 ◽

Vol 762 (1) ◽

pp. 165-178 ◽

Cited By ~ 1

Author(s):

CATHERINE M. OWCZAREK ◽

MEREDITH J. LAYTON ◽

DONALD METCALF ◽

ROSLYN CLARK ◽

NICHOLAS M. GOUGH ◽

...

Keyword(s):

Receptor Binding ◽

Leukemia Inhibitory Factor ◽

Inhibitory Factor ◽

Human Receptor

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Pembuatan Protokol Penapisan Virtual Berbasis Stuktur (pvbs) untuk Identifikasi Ligan Inhibitor Reseptor Platelet-Activating Factor (PAF-r) sebagai Target Terapeutik Asma menggunakan YASARA

Jurnal Riset Kimia ◽

10.25077/jrk.v11i1.346 ◽

2020 ◽

Vol 11 (1) ◽

pp. 35-42

Author(s):

Gerry Nugraha ◽

Enade Perdana Istyastono

Keyword(s):

Crystal Structure ◽

Receptor Binding ◽

Therapeutic Potential ◽

Platelet Activating Factor ◽

Data Bank ◽

Time Interval ◽

Internal Validation ◽

Asthma Patients ◽

Screening Protocol ◽

Dynamics Simulations

Platelet-activating factor receptors (PAF-r) is known as one of the receptors that affect asthma, while the Y-21480 ligand is reported as an effective, specific, and active PAF-r antagonist for asthma patients. Research in building structure-based virtual screening protocol (SBVS) for identification of PAF-r ligand inhibitors has been performed, the receptor crystal structure was obtained from the Protein Data Bank (PDB ID: 5zkp), while the ligand used as a leading compound is Y-24180, obtained from U.S. National Library of Medicine. Interactions between ligands and receptors are observed through molecular dynamics simulations using the YASARA program at intervals up to 20 nanoseconds, ligand-receptor binding stability occurs after a time interval of 2 nanoseconds, the lowest ligand-receptor binding energy occurs at a time interval of 1,401 picoseconds. Internal validation by re-docking 1,000 times the ligand to receptor resulted in a value of Root Mean Square Deviation (RMSD) of 0.6037 Å, confirmed that SBVS protocol was accurately able to reproduce the Y-24180 ligand pose on the 5zkp crystal structure, the protocol can be used as a new approach for investigation or design of compounds that have therapeutic potential as anti-asthma.

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