Pub Date : 2024-02-01Epub Date: 2024-03-26DOI: 10.1080/10799893.2024.2332886
Arushi Chauhan, Jitender Singh, Namrata Sangwan, Pramod K Avti
Purpose: The G-protein coupled receptor (GPCR) family, implicated in neurological disorders and drug targets, includes the sensitive serotonin receptor subtype, 5-HT2B. The influence of sodium ions on ligand binding at the receptor's allosteric region is being increasingly studied for its impact on receptor structure.
Methods: High-throughput virtual screening of three libraries, specifically the Asinex-GPCR library, which contains 8,532 compounds and FDA-approved (2466 compounds) and investigational compounds (2731)) against the modeled receptor [4IB4-5HT2BRM] using the standard agonist/antagonist (Ergotamine/Methysergide), as previously selected from our studies based on ADMET profiling, and further on basis of binding free energy a single compound - dihydroergotamine is chosen.
Results: This compound displayed strong interactions with the conserved active site. Ions influence ligand binding, with stronger interactions (3-H-bonds and 1-π-bond around 3.35 Å) observed when an agonist and ions are present. Ions entry is guided by conserved motifs in helices III, IV, and VII, which regulate the receptor. Dihydroergotamine, the selected drug, showed binding variance based on ions presence/absence, affecting amino acid residues in these motifs. DCCM and PCA confirmed the stabilization of ligands, with a greater correlation (∼46.6%-PC1) observed with ions. Dihydroergotamine-modified interaction sites within the receptor necessary for activation, serving as a potential 5HT2BRM agonist. RDF analysis showed the sodium ions density around the active site during dihydroergotamine binding.
Conclusion: Our study provides insights into sodium ion mobility's role in controlling ligand binding affinity in 5HT2BR, offering therapeutic development insights.
{"title":"Mechanistic insights into sodium ion-mediated ligand binding affinity and modulation of 5-HT2B GPCR activity: implications for drug discovery and development.","authors":"Arushi Chauhan, Jitender Singh, Namrata Sangwan, Pramod K Avti","doi":"10.1080/10799893.2024.2332886","DOIUrl":"10.1080/10799893.2024.2332886","url":null,"abstract":"<p><strong>Purpose: </strong>The G-protein coupled receptor (GPCR) family, implicated in neurological disorders and drug targets, includes the sensitive serotonin receptor subtype, 5-HT2B. The influence of sodium ions on ligand binding at the receptor's allosteric region is being increasingly studied for its impact on receptor structure.</p><p><strong>Methods: </strong>High-throughput virtual screening of three libraries, specifically the Asinex-GPCR library, which contains 8,532 compounds and FDA-approved (2466 compounds) and investigational compounds (2731)) against the modeled receptor [4IB4-5HT<sub>2B</sub>R<sub>M</sub>] using the standard agonist/antagonist (Ergotamine/Methysergide), as previously selected from our studies based on ADMET profiling, and further on basis of binding free energy a single compound - dihydroergotamine is chosen.</p><p><strong>Results: </strong>This compound displayed strong interactions with the conserved active site. Ions influence ligand binding, with stronger interactions (3-H-bonds and 1-π-bond around 3.35 Å) observed when an agonist and ions are present. Ions entry is guided by conserved motifs in helices III, IV, and VII, which regulate the receptor. Dihydroergotamine, the selected drug, showed binding variance based on ions presence/absence, affecting amino acid residues in these motifs. DCCM and PCA confirmed the stabilization of ligands, with a greater correlation (∼46.6%-PC1) observed with ions. Dihydroergotamine-modified interaction sites within the receptor necessary for activation, serving as a potential 5HT<sub>2B</sub>R<sub>M</sub> agonist. RDF analysis showed the sodium ions density around the active site during dihydroergotamine binding.</p><p><strong>Conclusion: </strong>Our study provides insights into sodium ion mobility's role in controlling ligand binding affinity in 5HT<sub>2B</sub>R, offering therapeutic development insights.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140288408","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}
Autophagy is a dynamic intracellular process of protein degradation, which is mostly triggered by nutrient deprivation. This process initiates with the formation of autophagosomes, which they captu...
{"title":"The route of autophagy regulation by osteopontin: a review on the linking mechanisms","authors":"Zohreh Abdolvahabi, Samira Ezzati-Mobaser, Zahra Hesari","doi":"10.1080/10799893.2023.2291563","DOIUrl":"https://doi.org/10.1080/10799893.2023.2291563","url":null,"abstract":"Autophagy is a dynamic intracellular process of protein degradation, which is mostly triggered by nutrient deprivation. This process initiates with the formation of autophagosomes, which they captu...","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2023-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138632106","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}
Pub Date : 2023-12-11DOI: 10.1080/10799893.2023.2291566
Ugur Yazar, Ali Rıza Guvercin, Mahindokht Rouhikia, Mehmet Aktoklu, Mehmet Ali Demirci, Ibrahim Erbay, Ahmet Ayar
Cerebrolysin, an endogenous peptide with neuroprotective and neurotrophic properties, indicated to be beneficial on diabetic neuropathy by preliminary clinical and experimental studies but without ...
{"title":"Cerebrolysin provides effective protection on high glucose-induced neuropathy in cultured rat dorsal root ganglion neurons","authors":"Ugur Yazar, Ali Rıza Guvercin, Mahindokht Rouhikia, Mehmet Aktoklu, Mehmet Ali Demirci, Ibrahim Erbay, Ahmet Ayar","doi":"10.1080/10799893.2023.2291566","DOIUrl":"https://doi.org/10.1080/10799893.2023.2291566","url":null,"abstract":"Cerebrolysin, an endogenous peptide with neuroprotective and neurotrophic properties, indicated to be beneficial on diabetic neuropathy by preliminary clinical and experimental studies but without ...","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2023-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138632112","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}
Pub Date : 2023-12-09DOI: 10.1080/10799893.2023.2291562
Yao-Qing Liao, Bin-Bo Fang, Qing-Xia Wu, Wei-Ying Dong, Guan-Ming Deng
Current evidence suggests a high co-prevalence of hypertension and cervical cancer. Accordingly, blood pressure control is indicated during anti-tumor drug therapy in this patient population. Over ...
{"title":"Verapamil modulates NFAT2 to inhibit tumor growth and potentiates PD1ab immune checkpoint inhibitor therapy in cervical cancer treatment","authors":"Yao-Qing Liao, Bin-Bo Fang, Qing-Xia Wu, Wei-Ying Dong, Guan-Ming Deng","doi":"10.1080/10799893.2023.2291562","DOIUrl":"https://doi.org/10.1080/10799893.2023.2291562","url":null,"abstract":"Current evidence suggests a high co-prevalence of hypertension and cervical cancer. Accordingly, blood pressure control is indicated during anti-tumor drug therapy in this patient population. Over ...","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2023-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138567498","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}
Pub Date : 2023-12-01Epub Date: 2024-02-13DOI: 10.1080/10799893.2024.2303013
S K Thaslim Basha, S Mahaboob Basha, D Subba Rao, S Rasheed, M Varalakshmi, C Naga Raju
A series of new phosphorylated derivatives of didanosine were designed, synthesized and evaluated their anticancer effects on human breast cancer cells. Their binding affinities were evaluated against aromatase enzyme and the molecular docking studies demonstrated that 9a, 9h and 9i exhibited high binding interactions than the parent molecule (ddI) and other derivatives; evaluated the aromatase enzyme inhibition. The cell viability, cell proliferation, lactate dehydrogenase showed potential anti-proliferative in dose dependent manner, these results were well correlated with hoesch stain and DNA fragmentation on MDA-MB-231 breast cancer cell lines. Cytotoxicity results disclosed that tryptophan amino acid ester substituted derivative 9i showed potential cell death against MDA-MB-231 cancer cell lines. Furthermore, compound 9i has great potential significance for further investigations (in vivo).
{"title":"Synthesis, <i>in silico</i> and <i>in vitro</i> anti-cancer studies of phosphorylated derivatives of didanosine targeting MDA-MB-231 breast cancer cell lines.","authors":"S K Thaslim Basha, S Mahaboob Basha, D Subba Rao, S Rasheed, M Varalakshmi, C Naga Raju","doi":"10.1080/10799893.2024.2303013","DOIUrl":"10.1080/10799893.2024.2303013","url":null,"abstract":"<p><p>A series of new phosphorylated derivatives of didanosine were designed, synthesized and evaluated their anticancer effects on human breast cancer cells. Their binding affinities were evaluated against aromatase enzyme and the molecular docking studies demonstrated that <b>9a</b>, <b>9h</b> and <b>9i</b> exhibited high binding interactions than the parent molecule (ddI) and other derivatives; evaluated the aromatase enzyme inhibition. The cell viability, cell proliferation, lactate dehydrogenase showed potential anti-proliferative in dose dependent manner, these results were well correlated with hoesch stain and DNA fragmentation on MDA-MB-231 breast cancer cell lines. Cytotoxicity results disclosed that tryptophan amino acid ester substituted derivative <b>9i</b> showed potential cell death against MDA-MB-231 cancer cell lines. Furthermore, compound <b>9i</b> has great potential significance for further investigations (<i>in vivo</i>).</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139472730","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}
Pub Date : 2023-12-01Epub Date: 2024-02-13DOI: 10.1080/10799893.2023.2291559
Abdolrahim Pourparizi, Mina Vazirinia, Fatemeh Pourrajab, Hamid Nadri, Asghar Davood
Purpose: Oxidative stress can damage cells and cause age-related illnesses such as Alzheimer's, Parkinson's, and Huntington's. This study looked at newly synthesized isoindole derivatives and their effects on SH-SY5Y as a neuroblastoma cell under oxidative stress through the NRF2 signaling pathway. NRF2 transcription factor plays a vital role in the oxidative stress response and cellular homeostasis.
Method: Three isoindoline-dione derivatives were synthesized by reacting phthalic anhydrides with 4-(2-aminoethyl)-1-benzyl piperidine. Their structures were confirmed through FT-IR, NMR, and Mass spectroscopy. The derivatives were then tested on human SH-SY5Y cells under an oxidative stress model induced by hydrogen peroxide (H2O2). The cell viability, ROS levels, protein carbonyl content, and gene expression of NRF2 and phase II antioxidative enzymes were measured after 24 h.
Results: Three isoindoline derivatives (3a-3c) were observed to increase the viability of SH-SY5Y cells by protective against oxidative stress, reducing intracellular reactive oxygen species and carbonylated proteins, and increasing gene expression levels of NRF2 and associated genes such as NQO-1, and GSTK1.
Conclusion: Isoindoline derivatives demonstrated a neuroprotective effect on SH-SY5Y cells through various neuroprotective mechanisms, although more studies are needed.
{"title":"New synthetic derivatives of isoindoline-dione: synthesis, neuroprotection assay and impact on the expression level of oxidative stress-related genes in neuronal-like cell line.","authors":"Abdolrahim Pourparizi, Mina Vazirinia, Fatemeh Pourrajab, Hamid Nadri, Asghar Davood","doi":"10.1080/10799893.2023.2291559","DOIUrl":"10.1080/10799893.2023.2291559","url":null,"abstract":"<p><strong>Purpose: </strong>Oxidative stress can damage cells and cause age-related illnesses such as Alzheimer's, Parkinson's, and Huntington's. This study looked at newly synthesized isoindole derivatives and their effects on SH-SY5Y as a neuroblastoma cell under oxidative stress through the NRF2 signaling pathway. NRF2 transcription factor plays a vital role in the oxidative stress response and cellular homeostasis.</p><p><strong>Method: </strong>Three isoindoline-dione derivatives were synthesized by reacting phthalic anhydrides with 4-(2-aminoethyl)-1-benzyl piperidine. Their structures were confirmed through FT-IR, NMR, and Mass spectroscopy. The derivatives were then tested on human SH-SY5Y cells under an oxidative stress model induced by hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>). The cell viability, ROS levels, protein carbonyl content, and gene expression of NRF2 and phase II antioxidative enzymes were measured after 24 h.</p><p><strong>Results: </strong>Three isoindoline derivatives <b>(3a-3c)</b> were observed to increase the viability of SH-SY5Y cells by protective against oxidative stress, reducing intracellular reactive oxygen species and carbonylated proteins, and increasing gene expression levels of NRF2 and associated genes such as NQO-1, and GSTK1.</p><p><strong>Conclusion: </strong>Isoindoline derivatives demonstrated a neuroprotective effect on SH-SY5Y cells through various neuroprotective mechanisms, although more studies are needed.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139545446","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}
Pub Date : 2023-12-01Epub Date: 2024-02-13DOI: 10.1080/10799893.2023.2298903
Oluwayimika Ibitoye, Mahmoud A A Ibrahim, Mahmoud E S Soliman
Triple-negative breast cancer (TNBC) is associated with high-grade invasive carcinoma leading to a 10% to 15% death rate in younger premenopausal women. Targeting cancerous inhibitors of protein phosphatase (CIP2A) has been a highly effective approach for exploring therapeutic drug candidates. Lapatinib, a dual tyrosine kinase inhibitor, has shown promising inhibition properties by inducing apoptosis in TNBC carcinogenesis in vivo. Despite knowledge of the 3D structure of CIP2A, no reports provide insight into CIP2A ligand binding sites. To this effect, we conducted in silico site identification guided by lapatinib binding. Four of the five sites identified were cross-validated, and the stem domain revealed more excellent ligand binding affinity. The binding affinity of lapatinib in these sites was further computed using the Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) approach. According to MM/PBSA//200 ns MD simulations, lapatinib exhibited a higher binding affinity against CIP2A in site 2 with ΔG critical values of -37.1 kcal/mol. The steadiness and tightness of lapatinib with CIP2A inside the stem domain disclosed glutamic acid-318 as the culprit amino acid with the highest electrostatic energy. These results provide clear information on the CIP2A domain capable of ligand binding and validate lapatinib as a promising CIP2A inhibitor in TNBC carcinogenesis.
{"title":"Exploring the composition of protein-ligand binding sites for cancerous inhibitor of PP2A (CIP2A) by inhibitor guided binding analysis: paving a new way for the Discovery of drug candidates against triple negative breast cancer (TNBC).","authors":"Oluwayimika Ibitoye, Mahmoud A A Ibrahim, Mahmoud E S Soliman","doi":"10.1080/10799893.2023.2298903","DOIUrl":"10.1080/10799893.2023.2298903","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) is associated with high-grade invasive carcinoma leading to a 10% to 15% death rate in younger premenopausal women. Targeting cancerous inhibitors of protein phosphatase (CIP2A) has been a highly effective approach for exploring therapeutic drug candidates. Lapatinib, a dual tyrosine kinase inhibitor, has shown promising inhibition properties by inducing apoptosis in TNBC carcinogenesis <i>in vivo</i>. Despite knowledge of the 3D structure of CIP2A, no reports provide insight into CIP2A ligand binding sites. To this effect, we conducted <i>in silico</i> site identification guided by lapatinib binding. Four of the five sites identified were cross-validated, and the stem domain revealed more excellent ligand binding affinity. The binding affinity of lapatinib in these sites was further computed using the Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) approach. According to MM/PBSA//200 ns MD simulations, lapatinib exhibited a higher binding affinity against CIP2A in site 2 with Δ<i>G</i> critical values of -37.1 kcal/mol. The steadiness and tightness of lapatinib with CIP2A inside the stem domain disclosed glutamic acid-318 as the culprit amino acid with the highest electrostatic energy. These results provide clear information on the CIP2A domain capable of ligand binding and validate lapatinib as a promising CIP2A inhibitor in TNBC carcinogenesis.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139087325","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}
Objective: This study investigated the effects of microRNA-124a on the differentiation of bone marrow mesenchymal stem cells (BMSCs) and its underlying mechanism.
Methods: Flow cytometry was used for isolation and identification of BMSCs. Real-time polymerase chain reaction (RT-PCR) was used to detect gene mRNA expression. Apoptosis was detected using Annexin V-FITC/PI Apoptosis Detection Kit. Cell proliferation ability was tested using Cell Counting Kit-8 (CCK-8). The differentiation of BMSCs into neuron inducers β-thiol ethanol or baicalin formed the basis of the study.
Results: β-thiol ethanol markedly suppressed the microRNA-124a expression of BMSCs, baicalin markedly induced the microRNA-124a expression of BMSCs and β-thiol ethanol or baicalin promoted apoptosis and reduced the growth of BMSCs. Only the microRNA-124a inhibitor did not affect apoptosis or the differentiation of BMSCs, and it increased the effects of β-thiol ethanol or baicalin on the apoptosis of BMSCs.
Conclusion: β-thiol ethanol and baicalin treatment could affect microRNA-124a expression in BMSCs. We demonstrated that microRNA-124a promoted the differentiation of BMSCs into neurons.
{"title":"MicroRNA-124a regulates the differentiation of bone marrow mesenchymal stem cells into neurons.","authors":"Eryi Zhao, Daimei Wang, Lijun Jing, Zhongyan Zhao, Shixiong Huang, Ling Xie, Shijun Hu, Hui Liang, Yanquan Chen","doi":"10.1080/10799893.2024.2303014","DOIUrl":"10.1080/10799893.2024.2303014","url":null,"abstract":"<p><strong>Objective: </strong>This study investigated the effects of microRNA-124a on the differentiation of bone marrow mesenchymal stem cells (BMSCs) and its underlying mechanism.</p><p><strong>Methods: </strong>Flow cytometry was used for isolation and identification of BMSCs. Real-time polymerase chain reaction (RT-PCR) was used to detect gene mRNA expression. Apoptosis was detected using Annexin V-FITC/PI Apoptosis Detection Kit. Cell proliferation ability was tested using Cell Counting Kit-8 (CCK-8). The differentiation of BMSCs into neuron inducers β-thiol ethanol or baicalin formed the basis of the study.</p><p><strong>Results: </strong>β-thiol ethanol markedly suppressed the microRNA-124a expression of BMSCs, baicalin markedly induced the microRNA-124a expression of BMSCs and β-thiol ethanol or baicalin promoted apoptosis and reduced the growth of BMSCs. Only the microRNA-124a inhibitor did not affect apoptosis or the differentiation of BMSCs, and it increased the effects of β-thiol ethanol or baicalin on the apoptosis of BMSCs.</p><p><strong>Conclusion: </strong>β-thiol ethanol and baicalin treatment could affect microRNA-124a expression in BMSCs. We demonstrated that microRNA-124a promoted the differentiation of BMSCs into neurons.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139472727","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}
Pub Date : 2023-10-01Epub Date: 2024-01-23DOI: 10.1080/10799893.2023.2298899
Mikael Ham Sembiring, Okta Nursanti, Tesia Aisyah Rahmania
Acetylcholinesterase (AChE) is a cholinergic enzyme that plays an essential role in the autonomic nervous system. This enzyme is often the target of many nerve agents. When this enzyme is inhibited, its function to hydrolyze acetylcholine is stopped, accumulating the acetylcholine in the tissue and causing prolonged stimulation. Some of the significant nerve agents include sarin (GB), soman (GD), tabun (GA), and venomous agent (VX). In order to determine which compound is the most stable and has the best affinity, the nerve agent venomous agent (VX), sarin (GB), soman (GD), and tabun (GA) are docked to the acetylcholinesterase (AChE) enzyme. After that, toxicity tests will be performed on 17 targets for the compound that was chosen. Autodock Vina 1.2.0 is the software used for the docking procedure. should use the Pymol program version 2.5.4 for analysis and the Ligplot software version 2.2 for visualization of the docking findings. The 'Tox Prediction' algorithm from Insilico was used to determine the toxicity of various substances. Based on the results of molecular docking, the free binding energy of Donepezil, sarin (GB), soman (GD), tabun (GA), and venomous agent (VX) in kcal/mol are -12,3, -4.8, -6.0, -5,1, and -6.3 respectively. Finally, four ligands bind strongly to the receptor Donepezil at RMSD 0.327 Å, and the venomous agent (VX) compound binds the most strongly compared to the other test ligands. Furthermore, in the toxicity test of Compound VX, which exhibits neurotoxic activity, no toxic activity was observed on specific organs and targets.
{"title":"Molecular docking and toxicity studies of nerve agents against acetylcholinesterase (AChE).","authors":"Mikael Ham Sembiring, Okta Nursanti, Tesia Aisyah Rahmania","doi":"10.1080/10799893.2023.2298899","DOIUrl":"10.1080/10799893.2023.2298899","url":null,"abstract":"<p><p>Acetylcholinesterase (AChE) is a cholinergic enzyme that plays an essential role in the autonomic nervous system. This enzyme is often the target of many nerve agents. When this enzyme is inhibited, its function to hydrolyze acetylcholine is stopped, accumulating the acetylcholine in the tissue and causing prolonged stimulation. Some of the significant nerve agents include sarin (GB), soman (GD), tabun (GA), and venomous agent (VX). In order to determine which compound is the most stable and has the best affinity, the nerve agent venomous agent (VX), sarin (GB), soman (GD), and tabun (GA) are docked to the acetylcholinesterase (AChE) enzyme. After that, toxicity tests will be performed on 17 targets for the compound that was chosen. Autodock Vina 1.2.0 is the software used for the docking procedure. should use the Pymol program version 2.5.4 for analysis and the Ligplot software version 2.2 for visualization of the docking findings. The 'Tox Prediction' algorithm from Insilico was used to determine the toxicity of various substances. Based on the results of molecular docking, the free binding energy of Donepezil, sarin (GB), soman (GD), tabun (GA), and venomous agent (VX) in kcal/mol are -12,3, -4.8, -6.0, -5,1, and -6.3 respectively. Finally, four ligands bind strongly to the receptor Donepezil at RMSD 0.327 Å, and the venomous agent (VX) compound binds the most strongly compared to the other test ligands. Furthermore, in the toxicity test of Compound VX, which exhibits neurotoxic activity, no toxic activity was observed on specific organs and targets.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139377902","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}
This study aims to develop a QSAR model for Antitubercular activity. The quantitative structure-activity relationship (QSAR) approach predicted the thiazolidine-4-ones derivative's Antitubercular activity. For the QSAR study, 53 molecules with Antitubercular activity on H37Rv were collected from the literature. Compound structures were drawn by ACD/Labs ChemSketch. The energy minimization of the 2D structure was done using the MM2 force field in Chem3D pro. PaDEL Descriptor software was used to construct the molecular descriptors. QSARINS software was used in this work to develop the 2D QSAR model. A series of thiazolidine 4-one with MIC data were taken from the literature to develop the QSAR model. These compounds were split into a training set (43 compounds) and a test set (10 compounds). The PaDEL software calculated 2300 descriptors for this series of thiazolidine 4-one derivatives. The best predictive Model 4, which has R2 of 0.9092, R2adj of 0.8950 and LOF parameter of 0.0289 identify a preferred fit. The QSAR study resulted in a stable, predictive, and robust model representing the original dataset. In the QSAR equation, the molecular descriptor of MLFER_S, GATSe2, Shal, and EstateVSA 6 positively correlated with Antitubercular activity. While the SpMAD_Dzs 6 is negatively correlated with Antitubercular activity. The high polarizability, Electronegativities, Surface area contributions and number of Halogen atoms in the thiazolidine 4-one derivatives will increase the Antitubercular activity.
{"title":"Quantitative structure activity relationship (QSAR) modeling study of some novel thiazolidine 4-one derivatives as potent anti-tubercular agents.","authors":"Anguraj Moulishankar, Sundarrajan Thirugnanasambandam","doi":"10.1080/10799893.2023.2281671","DOIUrl":"10.1080/10799893.2023.2281671","url":null,"abstract":"<p><p>This study aims to develop a QSAR model for Antitubercular activity. The quantitative structure-activity relationship (QSAR) approach predicted the thiazolidine-4-ones derivative's Antitubercular activity. For the QSAR study, 53 molecules with Antitubercular activity on H37Rv were collected from the literature. Compound structures were drawn by ACD/Labs ChemSketch. The energy minimization of the 2D structure was done using the MM2 force field in Chem3D pro. PaDEL Descriptor software was used to construct the molecular descriptors. QSARINS software was used in this work to develop the 2D QSAR model. A series of thiazolidine 4-one with MIC data were taken from the literature to develop the QSAR model. These compounds were split into a training set (43 compounds) and a test set (10 compounds). The PaDEL software calculated 2300 descriptors for this series of thiazolidine 4-one derivatives. The best predictive Model 4, which has <i>R</i><sup>2</sup> of 0.9092, <i>R</i><sup>2</sup>adj of 0.8950 and LOF parameter of 0.0289 identify a preferred fit. The QSAR study resulted in a stable, predictive, and robust model representing the original dataset. In the QSAR equation, the molecular descriptor of MLFER_S, GATSe2, Shal, and EstateVSA 6 positively correlated with Antitubercular activity. While the SpMAD_Dzs 6 is negatively correlated with Antitubercular activity. The high polarizability, Electronegativities, Surface area contributions and number of Halogen atoms in the thiazolidine 4-one derivatives will increase the Antitubercular activity.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138291257","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}