Journal of Receptors and Signal Transduction最新文献

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The combined use of thymoquinone and metformin provides more effective neuroprotection in a mouse model of MPTP-induced Parkinson's disease. 在 MPTP 诱导的帕金森病小鼠模型中,联合使用胸腺醌和二甲双胍可提供更有效的神经保护。
IF 2.6 4区 生物学
Journal of Receptors and Signal Transduction Pub Date : 2024-10-01 Epub Date: 2024-11-25 DOI: 10.1080/10799893.2024.2434112
Oguzhan Kavrik, Nurhan Gumral, Ozlem Ozmen, Rahime Aslankoc, Mustafa Saygin, Arzu Yalcin
{"title":"The combined use of thymoquinone and metformin provides more effective neuroprotection in a mouse model of MPTP-induced Parkinson's disease.","authors":"Oguzhan Kavrik, Nurhan Gumral, Ozlem Ozmen, Rahime Aslankoc, Mustafa Saygin, Arzu Yalcin","doi":"10.1080/10799893.2024.2434112","DOIUrl":"10.1080/10799893.2024.2434112","url":null,"abstract":"<p><p>Thymoquinone (TQ) is known for its antioxidant properties, and although metformin (MM) is known as an antidiabetic drug, it is suggested that it reduces neurodegeneration. The study aimed to investigate the neuroprotective effects of TQ and MM, particularly when used together, in relation to Parkinson's disease (PD). In the study, sixty-eight male C57BL/6 mice weighing 25-30 g were divided into five groups as follows: control, MPTP, MPTP+TQ, MPTP+MM, and MPTP+TQ+MM. MM (500 mg/kg, orally) and TQ (5 mg/kg, i.p.) were administered for 21 days. Motor coordination and locomotor activities were evaluated by the pole test. TOS and TAS analyses were conducted to determine oxidative stress levels in the substantia nigra. Dopaminergic degeneration in the substantia nigra was evaluated by analyzing Tyrosine hydroxylase (TH). To evaluate the apoptotic pathway, the expression levels of iNOS, BDNF, Complex 1, Bax, Bcl-2, Cytochrome C, AIF, and Caspase-3 were examined immunohistochemically. Compared to the MPTP-treated group, TQ, MM and MM+TQ treatment provided significant improvement in locomotor activity in mice, significantly increased antioxidant activity, significantly reduced the expression levels of iNOS, Bax, Cytochrome C, Caspase-3, and AIF, significantly increased BDNF, Bcl-2, and Complex 1 expressions, and significantly increased the number of TH positive cells. The separate use of TQ and MM exhibits neuroprotective activity, however, we showed that using TQ and MM in combination may be more effective. This may provide preclinical evidence supporting the therapeutic potential of their combined use for treating PD.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":" ","pages":"161-173"},"PeriodicalIF":2.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142716412","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Effect of dapagliflozin on pulmonary vascular remodeling in rats with chronic hypoxic pulmonary arterial hypertension. 达格列净对慢性缺氧肺动脉高压大鼠肺血管重构的影响。
IF 2.6 4区 生物学
Journal of Receptors and Signal Transduction Pub Date : 2024-10-01 Epub Date: 2024-12-14 DOI: 10.1080/10799893.2024.2433083
Yi Xu, Wenxue Liang, Juan Huo, Ting Zhang, Tianpu Feng, Man Li, Zhemin Zhu, Ping Zhou, Shasha Zhu, Yingzhi Lu, Lei Wang
{"title":"Effect of dapagliflozin on pulmonary vascular remodeling in rats with chronic hypoxic pulmonary arterial hypertension.","authors":"Yi Xu, Wenxue Liang, Juan Huo, Ting Zhang, Tianpu Feng, Man Li, Zhemin Zhu, Ping Zhou, Shasha Zhu, Yingzhi Lu, Lei Wang","doi":"10.1080/10799893.2024.2433083","DOIUrl":"10.1080/10799893.2024.2433083","url":null,"abstract":"<p><strong>Objective: </strong>To investigate the effects of sodium-glucose co-transporter 2 inhibitor dapagliflozin on pulmonary vascular remodeling in a rat model of chronic hypoxic pulmonary arterial hypertension.</p><p><strong>Methods: </strong>Eighteen female Sprague-Dawley rats were divided into three groups: control (CON), chronic hypoxia (HYP), and chronic hypoxia + dapagliflozin. The HYP and dapagliflozin groups were subjected to hypoxia and received saline or dapagliflozin. The CON group was normoxic and received saline. Body weight and fasting blood glucose were measured, and after 21 days, lung and heart tissues were analyzed for pulmonary artery reconstruction and right ventricular hypertrophy. Western blotting assessed Bax and Bcl-2 protein levels.</p><p><strong>Results: </strong>Chronic hypoxia increased pulmonary artery wall thickness and lung fibrosis and caused right ventricular hypertrophy. Dapagliflozin reduced these changes, decreasing artery wall thickness, fibrosis, and hypertrophy while increasing the Bax/Bcl-2 ratio.</p><p><strong>Conclusion: </strong>Dapagliflozin alleviates chronic hypoxia-induced pulmonary artery wall thickening and lung tissue fibrosis in rats, potentially through proapoptotic effects.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":" ","pages":"174-180"},"PeriodicalIF":2.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142823834","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The cannabinoid CB2 receptor positive allosteric modulator EC21a exhibits complicated pharmacology in vitro. 大麻素 CB2 受体正异位调节剂 EC21a 在体外表现出复杂的药理学特性。
IF 2.6 4区 生物学
Journal of Receptors and Signal Transduction Pub Date : 2024-08-01 Epub Date: 2024-11-22 DOI: 10.1080/10799893.2024.2431986
Aidong Qi, Xueqing Han, Marc Quitalig, Jessica Wu, Plamen P Christov, KyuOk Jeon, Somnath Jana, Kwangho Kim, Darren W Engers, Craig W Lindsley, Alice L Rodriguez, Colleen M Niswender
{"title":"The cannabinoid CB<sub>2</sub> receptor positive allosteric modulator EC21a exhibits complicated pharmacology <i>in vitro</i>.","authors":"Aidong Qi, Xueqing Han, Marc Quitalig, Jessica Wu, Plamen P Christov, KyuOk Jeon, Somnath Jana, Kwangho Kim, Darren W Engers, Craig W Lindsley, Alice L Rodriguez, Colleen M Niswender","doi":"10.1080/10799893.2024.2431986","DOIUrl":"10.1080/10799893.2024.2431986","url":null,"abstract":"<p><p>Schizophrenia is a complex disease involving the dysregulation of numerous brain circuits and patients exhibit positive symptoms (hallucinations, delusions), negative symptoms (anhedonia), and cognitive impairments. We have shown that the antipsychotic efficacy of positive allosteric modulators (PAMs) of both the M<sub>4</sub> muscarinic receptor and metabotropic glutamate receptor 1 (mGlu<sub>1</sub>) involve the retrograde activation of the presynaptic cannabinoid type-2 (CB<sub>2</sub>) receptor, indicating that CB<sub>2</sub> activation or potentiation could result in a novel therapeutic strategy for schizophrenia. We used two complementary assays, receptor-mediated phosphoinositide hydrolysis and GIRK channel activation, to characterize a CB<sub>2</sub> PAM scaffold, represented by the compound EC21a, to explore its potential as a starting point to optimize therapeutics for schizophrenia. These studies revealed that EC21a acts as an allosteric inverse agonist at CB<sub>2</sub> in both assays and exhibits a mixed allosteric agonist/negative allosteric modulator profile at CB<sub>1</sub> depending upon the assay used for profiling. A series of compounds related to EC21a also functioned as CB<sub>2</sub> inverse agonists. Overall, these results suggest that EC21a exhibits complicated and potentially assay-dependent pharmacology, which may impact interpretation of <i>in vivo</i> studies.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":" ","pages":"151-159"},"PeriodicalIF":2.6,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11636628/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142687251","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Investigating the inhibitory potential of natural bioactive compounds against cyclin-dependent kinase 13: virtual high throughput screening and MD simulation studies to target CDK signaling. 研究天然生物活性化合物对细胞周期蛋白依赖性激酶 13 的抑制潜力:针对 CDK 信号转导的虚拟高通量筛选和 MD 模拟研究。
IF 2.6 4区 生物学
Journal of Receptors and Signal Transduction Pub Date : 2024-08-01 Epub Date: 2024-11-23 DOI: 10.1080/10799893.2024.2430495
Zehra, Farah Anjum, Talha Jawaid, Romana Ishrat, Md Imtaiyaz Hassan
{"title":"Investigating the inhibitory potential of natural bioactive compounds against cyclin-dependent kinase 13: virtual high throughput screening and MD simulation studies to target CDK signaling.","authors":"Zehra, Farah Anjum, Talha Jawaid, Romana Ishrat, Md Imtaiyaz Hassan","doi":"10.1080/10799893.2024.2430495","DOIUrl":"10.1080/10799893.2024.2430495","url":null,"abstract":"<p><p>Cyclin-dependent kinase 13 (CDK13) belongs to the cyclin-dependent kinase (CDK) family that is actively involved in transcription regulation and RNA splicing. CDK13 binds with its partner, cyclin K, to regulate several biological processes. CDK13 and cyclin K complex phosphorylates RNA pol II carboxyl-terminal domain (CTD) at several serine residues, creating transcription elongation. The upregulation of the kinase contributes to tumor growth and cell proliferation, and is highly associated with various cancers, including skin, stomach, and ovarian. Thus, it can be considered an efficient therapeutic target for the development of drugs against cancer. In this work, a virtual high throughput screening (vHTS) of the ZINC library was carried out to elucidate the initial potent compounds. Further, filters were applied to identify the hit compounds among the ∼90,000 compound library. Based on the docking scores and binding affinity, the top 100 hits were elucidated, and they were further narrowed down to 50 compounds based on ADMET and Lipinski's RO5 filter. Finally, 10 compounds were chosen that showed appreciable biological activity. Among them, ZINC02136558 was selected as a potent lead compound that showed strong interaction with the amino acid residues of active and binding sites of CDK13. Furthermore, the all-atom molecular dynamic simulation was performed at 200 ns to explore the dynamic evolution of the system. Finally, the results showed that the ZINC02136558 may be considered as a potential lead molecule to inhibit CDK13 and implicated in therapeutic management of cancer and associated diseases.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":" ","pages":"140-150"},"PeriodicalIF":2.6,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142693161","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Effect of elastin on abnormal proliferation of pulmonary artery smooth muscle cells at an early stage of hypoxic exposure. 弹性蛋白对缺氧早期肺动脉平滑肌细胞异常增殖的影响
IF 2.6 4区 生物学
Journal of Receptors and Signal Transduction Pub Date : 2024-08-01 Epub Date: 2024-11-26 DOI: 10.1080/10799893.2024.2430489
Hao Dong, Pengshuai Li, Xuefei Wang, Yuxin Zhang, Fei Han, Shan Gao, Weicao Hu, Xuewei Hao
{"title":"Effect of elastin on abnormal proliferation of pulmonary artery smooth muscle cells at an early stage of hypoxic exposure.","authors":"Hao Dong, Pengshuai Li, Xuefei Wang, Yuxin Zhang, Fei Han, Shan Gao, Weicao Hu, Xuewei Hao","doi":"10.1080/10799893.2024.2430489","DOIUrl":"10.1080/10799893.2024.2430489","url":null,"abstract":"<p><p>Elastin (Eln) is an extracellular matrix protein implicated in the proliferation of vascular smooth muscle cells. However, its potential role in hypoxic pulmonary hypertension (HPH) remains uncertain. This study is the first to demonstrate that elastin can promote the proliferation of mouse pulmonary artery smooth muscle cells (mPASMCs) and that hypoxia significantly induces Eln expression in cultured mPASMCs, thereby participating in the cell cycle. Interference with Eln expression <i>via</i> siRNA led to the downregulation of PCNA, Cyclin A, and Cyclin D, thus, the hypoxia-induced proliferation of mPASMCs was reversed. Furthermore, our study demonstrated that the hypoxia-induced expression of Eln and the proliferation of mPASMCs are associated with the proliferation-related phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway. In conclusion, these data suggest that Eln is a key regulatory factor in mPASMCs proliferation, potentially elucidating the mechanism underlying hypoxia-induced mPASMCs proliferation. This finding may offer valuable insights for the study of hypoxic pulmonary hypertension.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":" ","pages":"129-139"},"PeriodicalIF":2.6,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142716348","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
An in-silico approach - molecular docking analysis of flavonoids against GSK-3β and TNF-α targets in Alzheimer's disease. 针对阿尔茨海默病中 GSK-3β 和 TNF-α 靶点的黄酮类化合物的分子对接分析。
IF 2.6 4区 生物学
Journal of Receptors and Signal Transduction Pub Date : 2024-06-01 Epub Date: 2024-08-27 DOI: 10.1080/10799893.2024.2396430
Sittarthan Viswanathan, Rengaraj Sivaraj, A Hannah Rachel Vasanthi, Kavimani Subramanian, Vimalavathini Ramesh
{"title":"An <i>in-silico</i> approach - molecular docking analysis of flavonoids against GSK-3β and TNF-α targets in Alzheimer's disease.","authors":"Sittarthan Viswanathan, Rengaraj Sivaraj, A Hannah Rachel Vasanthi, Kavimani Subramanian, Vimalavathini Ramesh","doi":"10.1080/10799893.2024.2396430","DOIUrl":"10.1080/10799893.2024.2396430","url":null,"abstract":"<p><strong>Introduction: </strong>Drug development for Alzheimer's disease has one of the greatest failure rates of any therapeutic field and AD is still incurable. Glycogen synthase kinase-3β is a critical enzyme implicated in the pathogenesis of AD, particularly in the hyperphosphorylation of tau protein, which leads to the formation of neurofibrillary tangles. TNF-α also plays a significant role in the pathogenesis of Alzheimer's disease by promoting neuroinflammation, contributing to the formation of amyloid plaques and neurofibrillary tangles, impairing synaptic function, and disrupting the balance of neurotrophic factors. Phytomedicine has numerous advantages over synthetic medications, acting multiple mode of action, including being less toxic and having fewer adverse effects. Flavonoids act as a promising therapeutic target for treating Alzheimer's disease. The present work investigates the anti-AD potentials of 35 flavonoids for the inhibition of GSK-3β and TNF-α.</p><p><strong>Methods: </strong>The physicochemical, pharmacokinetic parameters, toxicity profile and drug-likeliness of the selected 35 flavonoids were predicted using SwissADME & OSIRIS data Warrier property explorer web tool. All flavonoids were selected for docking studies on GSK-3β and TNF-α protein using Autodock 4.2.1.</p><p><strong>Results: </strong>The predictions of this study suggested that among the selected 35 flavonoids, Top 3 flavonoids, such as Epicatechin gallate -10.93 kcal/mol, Fisetin -9.44 kcal/mol and Eriodictyol -8.54 kcal/mol for GSK-3β targets. TNF-α Fisetin -11.52 kcal/mol, Sterubin -10.87 kcal/mol, Biochainin A -10.69 kcal/mol were compared with standard drug donepezil.</p><p><strong>Conclusion: </strong>Therefore, these flavonoids could be utilized as possible leads for the structure-based design in the advancement of new, strong Anti-Alzheimer's agents. However, more <i>invitro</i> and <i>invivo</i> analyses are required to finally confirm the outcomes of this research.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":" ","pages":"73-81"},"PeriodicalIF":2.6,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142073131","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
UBE2C, targeted by miR-140-3p, promotes the progression of osteosarcoma via PI3K/AKT signaling pathway. miR-140-3p 靶向的 UBE2C 通过 PI3K/AKT 信号通路促进骨肉瘤的进展。
IF 2.6 4区 生物学
Journal of Receptors and Signal Transduction Pub Date : 2024-06-01 Epub Date: 2024-11-05 DOI: 10.1080/10799893.2024.2423100
Wenze Huang, Yan Zhou, Jing Ren, Chunfa Chen
{"title":"UBE2C, targeted by miR-140-3p, promotes the progression of osteosarcoma via PI3K/AKT signaling pathway.","authors":"Wenze Huang, Yan Zhou, Jing Ren, Chunfa Chen","doi":"10.1080/10799893.2024.2423100","DOIUrl":"10.1080/10799893.2024.2423100","url":null,"abstract":"<p><strong>Background: </strong>UBE2C was reported to play carcinogenic effects in diverse cancers. However, the role of UBE2C in osteosarcoma was poorly understood, and its functional mechanisms were not fully clarified.</p><p><strong>Methods: </strong>RT-qPCR was used to assess the expression of UBE2C mRNA and miR-140-3p, and western blot technique was used to examine the UBE2C protein and PI3K/AKT pathway-associated proteins. CCK-8 test was applied to measure cell proliferation, and wound healing assay were used to measure migration. Using animal studies, the function of UBE2C <i>in vivo</i> was evaluated. Dual-luciferase reporter assay was used to confirm the potential interaction among UBE2C and miR-140-3p.</p><p><strong>Results: </strong>In osteosarcoma cells as well as tumor samples, UBE2C was strongly expressed. Osteosarcoma cell proliferation as well as cell migration were inhibited by UBE2C knockdown, and PI3K/AKT signaling activity was diminished. In addition, UBE2C knockdown impeded tumor growth in animal models. UBE2C expression was lessened by miR-140-3p as miR-140-3p targets it. UBE2C is overexpressed which promote osteosarcoma proliferation as well as migration, and strengthened the PI3K/AKT signaling activity, while forced miR-140-3p expression partially abolished these effects.</p><p><strong>Conclusion: </strong>UBE2C, targeted by miR-140-3p, drove carcinogenic effects in osteosarcoma through activating the PI3K/AKT pathway.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":" ","pages":"107-114"},"PeriodicalIF":2.6,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582882","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Acetylcholinesterase - glucose-regulated protein 78 binding site prediction, a hope to cure neurological disorders such as Alzheimer's disease. 乙酰胆碱酯酶--葡萄糖调节蛋白 78 结合位点预测,有望治愈阿尔茨海默病等神经系统疾病。
IF 2.6 4区 生物学
Journal of Receptors and Signal Transduction Pub Date : 2024-06-01 Epub Date: 2024-11-10 DOI: 10.1080/10799893.2024.2426523
Ahmed M Ali, Ahmed A Mohamed, Ahmed N Ibrahim, Abdo A Elfiky
{"title":"Acetylcholinesterase - glucose-regulated protein 78 binding site prediction, a hope to cure neurological disorders such as Alzheimer's disease.","authors":"Ahmed M Ali, Ahmed A Mohamed, Ahmed N Ibrahim, Abdo A Elfiky","doi":"10.1080/10799893.2024.2426523","DOIUrl":"10.1080/10799893.2024.2426523","url":null,"abstract":"<p><p>Cerebral amyloid plaques in the brain define the elderly neuralgic disorder, Alzheimer's disease (AD). The enzyme Acetylcholinesterase (AChE) was reported to play a vital role in AD. It was shown that AChE induces amyloid fibril formation forming highly toxic AChE-Amyloid-β (Aβ) complexes. AChE can accelerate amyloid formation, and its inhibition could prevent such alterations to the enzyme. Understanding the proteostasis of AChE and its binding site to cellular chaperone GRP78 (Glucose-regulated protein 78) would help find a treatment for AD. In this study, the state of the art computational tools were utilized to predict the binding location of AChE that can stably associate with the cellular chaperone, GRP78. Sequence comparison along with molecular docking predicts two binding locations on AChE (C69-C96 and C257-C272) that could bind to GRP78 substrate binding domain β (SBDβ). The analysis of the docking data suggests that the former location has the best average binding affinity value (-12.16 kcal/mol) and average interaction pattern (13.9 ± 3.5 H-bonds, 5.5 ± 1.4 hydrophobic contacts, and 1.4 ± 1.2 salt bridges).</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":" ","pages":"122-128"},"PeriodicalIF":2.6,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142622685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Virtual screening, molecular docking and dynamics simulation studies to identify potential agonists of orphan receptor GPR78 targeting CNS disorders. 通过虚拟筛选、分子对接和动力学模拟研究,确定针对中枢神经系统疾病的孤儿受体 GPR78 的潜在激动剂。
IF 2.6 4区 生物学
Journal of Receptors and Signal Transduction Pub Date : 2024-06-01 Epub Date: 2024-09-24 DOI: 10.1080/10799893.2024.2405488
Vasavi Garisetti, Roslin Elsa Varughese, Arthikasree Anandamurthy, Jebiti Haribabu, Claudio Allard Garrote, Gayathri Dasararaju
{"title":"Virtual screening, molecular docking and dynamics simulation studies to identify potential agonists of orphan receptor GPR78 targeting CNS disorders.","authors":"Vasavi Garisetti, Roslin Elsa Varughese, Arthikasree Anandamurthy, Jebiti Haribabu, Claudio Allard Garrote, Gayathri Dasararaju","doi":"10.1080/10799893.2024.2405488","DOIUrl":"10.1080/10799893.2024.2405488","url":null,"abstract":"<p><p>G protein-coupled receptors (GPCRs) are important targets in drug discovery because of their roles in physiological and pathological processes. Orphan GPCRs are GPCR proteins for which endogenous ligands have not yet been identified and they present interesting avenues for therapeutic intervention. This study focuses on GPR78, an orphan GPCR that is expressed in the central nervous system and linked to neurological disorders. GPR78 has no reported crystal structure and there is limited research. In this study, we have predicted the three dimensional model of GPR78 and its probable binding pocket. Structure-based virtual screening was carried out using the ChemDiv and Enamine REAL databases, followed by induced-fit docking studies to identify potential lead compounds with favorable interactions. These lead compounds were then embedded into a POPC lipid bilayer for a 200 ns molecular dynamics simulation. Free energy landscapes and MM-PBSA analyses were performed to assess the binding energies and conformational dynamics. The results highlight the dynamic nature of GPR78 in the presence of lead compounds and show favorable binding interactions. This study aims to predict a reliable three dimensional model of GPR78 and identify novel lead compounds through a comprehensive <i>in silico</i> approach. The identification of these potential GPR78 agonists represents a significant step in the development of new therapeutics for neurological disorders, highlighting the therapeutic potential of orphan GPR78 in CNS disorders.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":" ","pages":"82-96"},"PeriodicalIF":2.6,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142307993","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Allosteric covalent inhibition of TOE1 as potential unexplored anti-cancer target: structure-based virtual screening and covalent molecular dynamics analysis. 作为潜在未开发抗癌靶点的 TOE1 的异位共价抑制:基于结构的虚拟筛选和共价分子动力学分析。
IF 2.6 4区 生物学
Journal of Receptors and Signal Transduction Pub Date : 2024-06-01 Epub Date: 2024-10-08 DOI: 10.1080/10799893.2024.2411690
Ibrahim Oluwatobi Kehinde, Ernest Oduro-Kwateng, Mahmoud E S Soliman
{"title":"Allosteric covalent inhibition of TOE1 as potential unexplored anti-cancer target: structure-based virtual screening and covalent molecular dynamics analysis.","authors":"Ibrahim Oluwatobi Kehinde, Ernest Oduro-Kwateng, Mahmoud E S Soliman","doi":"10.1080/10799893.2024.2411690","DOIUrl":"10.1080/10799893.2024.2411690","url":null,"abstract":"<p><p>Cancer remains a formidable challenge in therapeutic development owing to its complex molecular mechanisms and resistance to conventional treatments. Recent evidence suggests that TOE1 may play a role in cancer progression, making it an attractive target for therapeutic interventions, nevertheless, very limited research in literature has explored the potential of TOE1 inhibitors as anti-cancer. Herein, by exploring a library of 13,900 cysteine-targeted covalent inhibitors <i>via</i> a comprehensive virtual screening process, we sought to identify potential compounds that could be developed into effective cancer therapies against TOE1. The compounds were first screened based on their binding affinity, followed by their compliance with drug-like properties, and finally, by their effective covalent modeling to a reactive cysteine (Cys80). A total of 66 compounds, 28 compounds, and 3 compounds were found to have higher binding affinities, optimum drug-likeness, and higher covalent docking scores, respectively, than the reference compound. The top three screened compounds, 0462, 2204, and 7034, demonstrated favorable interaction profiles, covalent binding dynamics, free binding energetics, and per-residue energy contributions as compared to the reference compound. Notably, compound 0462 contributed to the highest free binding energy and significantly enhanced the stability and rigidity of TOE1, while restricting residue flexibility. This study provides an account of the molecular mechanics underpinning the covalent inhibition of TOE1, while providing a compelling case for further investigation and translation of the screened TOE1 inhibitors, particularly compound 0462, as novel therapeutics against cancer.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":" ","pages":"97-106"},"PeriodicalIF":2.6,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142391390","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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