Possible Mechanism of Action of Neurokinin-1 Receptors (NK1R) Antagonists

Ozturk, Ozum; Akı-Yalçın, Esin; Ertan-Bolelli, Tuğba; Bolelli, Kayhan; Nur-Hidayat, Andry; Bingöl-Ozakpinar, Özlem; Özdemir, Filiz; Yalçın, İsmail

doi:10.17265/2328-2150/2017.11.001

Cited by 3 publications

(2 citation statements)

References 31 publications

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“…Site 1 was subjected to docking studies based on the D score and site score obtained earlier. Glide Ligand docking module [28][29][30]. One of the most important amino acids needed for antagonistic activity of NK1R, GLU 165 was seen to be interacting with l-NAT as seen in Fig.…”

Section: Molecular Docking Studies With Nk1rmentioning

confidence: 99%

In silico screening of neurokinin receptor antagonists as a therapeutic strategy for neuroinflammation in Alzheimer’s disease

et al. 2021

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Neuroinflammation is one of the detrimental factors leading to neurodegeneration in Alzheimer’s disease (AD) and other neurodegenerative disorders. The activation of microglial neurokinin 1 receptor (NK1R) by substance P (SP) enhances neuroinflammation which is mediated through pro-inflammatory pathways involving NFkB, ERK1/2, and P38 and thus projects the scope and importance of NK1R inhibitors. Emphasizing the inhibitory role of N Acetyl l Tryptophan (l-NAT) on NK1R, this is the first in silico screening of l-NAT mediated NK1R antagonism. In addition, FDA- approved ligands were screened for their potential NK1R antagonism. The l-NAT was docked in XP (Extra Precision) mode while FDA-approved ligands were screened in HTVS (High Throughput Virtual Screening), SP (Standard Precision), and XP mode onto NK1R (PDB:6HLO). The l-NAT and top 3 compounds FDA-approved ligands were subjected to molecular dynamics (MD) studies of 100 ns simulation time. The XP docking of l-NAT, indacaterol, modafinil and alosetron showed good docking scores. Their 100 ns MD showed brief protein–ligand interactions with an acceptable root mean square deviation. The protein–ligand contacts depicted pi-pi stacking, pi-cation, hydrogen bonds, and water bridges with the amino acids necessary for NK1R inhibition. The variable colour band intensities on the protein–ligand contact map indicated their binding strength with amino acids. The molecular mechanics/generalized born surface area (MM-GBSA) scores suggested favourable binding free energy of the complexes. Thus, our study predicted the ability of l-NAT, indacaterol, modafinil, and alosetron as capable NK1R inhibitors that can aid to curb neuroinflammation in conditions of AD which could be further ascertained in subsequent studies. Graphic Abstract

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Section: Molecular Docking Studies With Nk1rmentioning

confidence: 99%

In silico screening of neurokinin receptor antagonists as a therapeutic strategy for neuroinflammation in Alzheimer’s disease

et al. 2021

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“…As the leading central member of the TK family, SP has higher binding affinities to NK1R [ 7 , 9 ]. It is well-known that SP is commonly presented in peripheral and central nervous systems, thereby playing an important role in regulating neurogenic inflammation and immune responses [ 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

Investigation of the Role of Neurokinin-1 Receptor Inhibition Using Aprepitant in the Apoptotic Cell Death through PI3K/Akt/NF-κB Signal Transduction Pathways in Colon Cancer Cells

Ghahremanloo

Javid

Afshari

et al. 2021

BioMed Research International

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Background. Colorectal cancer (CRC) is recognized as one of the most common malignancies with a high mortality rate worldwide, supporting the necessity for an effective novel antitumor drug to improve current therapy’s effectiveness. Substance P (SP) is the essential member of the tachykinins (TKs) family, which binds to the specific receptors, known as neurokinin-1 receptor (NK1R), exerting its multiple influences such as tumor cell proliferation, angiogenesis, and metastasis. Aprepitant, as a specific NK1R antagonist, is suggested as a novel antitumor agent, promoting apoptotic processes in tumor cells; however, the exact antitumor mechanism of aprepitant on molecular signaling in CRC is not entirely known. Method. The resazurin assay was conducted to assess the cytotoxic effects of aprepitant on the viability of the CRC cell line (SW480). The level of reactive oxygen species (ROS) was measured after 24-hour treatment with SP and aprepitant. PI/annexin V-FITC staining was conducted to assess apoptosis. Also, the expression of NF-κB antiapoptotic target genes and proapoptotic p53 target genes was measured by real-time- (RT-) PCR assay. Western blotting assay was performed to determine the expression of PI3k/AKT/NF-κB proteins. Results. We found that aprepitant stimulates apoptotic cell death and attenuates the PI3K/Akt pathway and its downstream proapoptotic target gene, including NF-κB in SW480 cells. Also, the obtained results from the quantitative RT-PCR assay showed that aprepitant could decrease the level of mRNA of NF-κB antiapoptotic target genes. Conclusion. Towards this end, this study suggests that SP/NK1R system plays a vital role in the development of CRC, and pharmaceutical targeting of NK1R using aprepitant might be a promising treatment against CRC.

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Prediction of adsorption capacity and biodegradability of polybrominated diphenyl ethers in soil

Cantwell

Song

et al. 2022

Environ Sci Pollut Res

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Possible Mechanism of Action of Neurokinin-1 Receptors (NK1R) Antagonists

Cited by 3 publications

References 31 publications

In silico screening of neurokinin receptor antagonists as a therapeutic strategy for neuroinflammation in Alzheimer’s disease

In silico screening of neurokinin receptor antagonists as a therapeutic strategy for neuroinflammation in Alzheimer’s disease

Investigation of the Role of Neurokinin-1 Receptor Inhibition Using Aprepitant in the Apoptotic Cell Death through PI3K/Akt/NF-κB Signal Transduction Pathways in Colon Cancer Cells

Prediction of adsorption capacity and biodegradability of polybrominated diphenyl ethers in soil

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