Chujie Zhang, Juncong Ma, Chang Liu, Xianliang Yan
Sepsis-induced acute lung injury (ALI) is a severe complication of sepsis. Karanjin, a natural flavonoid compound, has been proved to have anti-inflammatory function, but its role in sepsis-stimulated ALI is uncertain. Herein, the effect of karanjin on sepsis-stimulated ALI was investigated. We built a mouse model of lipopolysaccharide (LPS)-stimulated ALI. The histopathological morphology of lung tissues was scrutinized by hematoxylin–eosin (H&E) staining. The lung injury score and lung wet/dry weight ratio were detected. The myeloperoxidase (MPO) activity and malondialdehyde (MDA) content were scrutinized by commercial kits. Murine alveolar lung epithelial (MLE-12) cells were treated with LPS to mimic a cellular model of ALI. The cell viability was scrutinized by the CCK-8 assay. The contents of proinflammatory cytokines were scrutinized by qRT-PCR and ELISA. The TLR4 and MyD88 contents were scrutinized by qRT-PCR and western blotting. Results showed that karanjin alleviated LPS-stimulated ALI in mice by inhibiting lung tissue lesions, edema, and oxidative stress. Moreover, karanjin inhibited LPS-stimulated inflammation and TLR4 pathway activation in mice. However, treatment with GSK1795091, an agonist of TLR4, attenuated the effects of karanjin on LPS-induced ALI. Furthermore, karanjin repressed LPS-stimulated inflammatory response and TLR4 pathway activation in MLE-12 cells. Overexpression of TLR4 attenuated karanjin effects on LPS-stimulated inflammatory responses in MLE-12 cells. In conclusion, karanjin repressed sepsis-stimulated ALI in mice by suppressing the TLR4 pathway.
{"title":"The protective effect of karanjin against sepsis-induced acute lung injury in mice is involved in the suppression of the TLR4 pathway","authors":"Chujie Zhang, Juncong Ma, Chang Liu, Xianliang Yan","doi":"10.1111/cbdd.14579","DOIUrl":"10.1111/cbdd.14579","url":null,"abstract":"<p>Sepsis-induced acute lung injury (ALI) is a severe complication of sepsis. Karanjin, a natural flavonoid compound, has been proved to have anti-inflammatory function, but its role in sepsis-stimulated ALI is uncertain. Herein, the effect of karanjin on sepsis-stimulated ALI was investigated. We built a mouse model of lipopolysaccharide (LPS)-stimulated ALI. The histopathological morphology of lung tissues was scrutinized by hematoxylin–eosin (H&E) staining. The lung injury score and lung wet/dry weight ratio were detected. The myeloperoxidase (MPO) activity and malondialdehyde (MDA) content were scrutinized by commercial kits. Murine alveolar lung epithelial (MLE-12) cells were treated with LPS to mimic a cellular model of ALI. The cell viability was scrutinized by the CCK-8 assay. The contents of proinflammatory cytokines were scrutinized by qRT-PCR and ELISA. The TLR4 and MyD88 contents were scrutinized by qRT-PCR and western blotting. Results showed that karanjin alleviated LPS-stimulated ALI in mice by inhibiting lung tissue lesions, edema, and oxidative stress. Moreover, karanjin inhibited LPS-stimulated inflammation and TLR4 pathway activation in mice. However, treatment with GSK1795091, an agonist of TLR4, attenuated the effects of karanjin on LPS-induced ALI. Furthermore, karanjin repressed LPS-stimulated inflammatory response and TLR4 pathway activation in MLE-12 cells. Overexpression of TLR4 attenuated karanjin effects on LPS-stimulated inflammatory responses in MLE-12 cells. In conclusion, karanjin repressed sepsis-stimulated ALI in mice by suppressing the TLR4 pathway.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141629579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Elaine Soares Coimbra, Luciana M. R. Antinarelli, Ari Sérgio de Oliveira Lemos, Adolfo Firmino da Silva Neto, Alessandra Campbell Pinheiro, Marcus Vinícius Nora de Souza
Leishmaniasis is a disease caused by protozoa Leishmania spp., considered as a significant and urgent public health problem mainly in developing countries. In the absence of an effective vaccine, the treatment of infected people is one of the most commonly prophylactic measures used to control this disease. However, the therapeutic arsenal is reduced to a few drugs, with serious side effects and variability in efficacy. Attempting to this problem, in this work, a series of benzothiazole derivatives was synthetized and assayed against promastigotes and intracellular amastigotes of L. amazonensis, as well as the toxicity on macrophages. In addition, studies about the mechanism of action were also performed. Among the synthesized molecules, the substitution at position 4 of the aromatic ring appears to be critical for activity. The best compound exhibited IC50 values of 28.86 and 7.70 μM, against promastigotes and amastigotes of L. amazonensis, respectively, being more active than miltefosine, used as reference drug. The in silico analysis of physicochemical and pharmacokinetic (ADMET) properties of this compound suggested a good profile of oral bioavailability and safety. In conclusion, the strategy of using benzothiazole nucleous in the search for new antileishmanial agents was advantageous and preliminar data provide information about the mechanism of action as well as in silico parameters suggest a good profile for preclinical studies.
{"title":"Synthesis, biological evaluation and mechanism of action of benzothiazole derivatives with aromatic hydrazone moiety, a new class of antileishmanial compounds","authors":"Elaine Soares Coimbra, Luciana M. R. Antinarelli, Ari Sérgio de Oliveira Lemos, Adolfo Firmino da Silva Neto, Alessandra Campbell Pinheiro, Marcus Vinícius Nora de Souza","doi":"10.1111/cbdd.14585","DOIUrl":"10.1111/cbdd.14585","url":null,"abstract":"<p>Leishmaniasis is a disease caused by protozoa <i>Leishmania</i> spp., considered as a significant and urgent public health problem mainly in developing countries. In the absence of an effective vaccine, the treatment of infected people is one of the most commonly prophylactic measures used to control this disease. However, the therapeutic arsenal is reduced to a few drugs, with serious side effects and variability in efficacy. Attempting to this problem, in this work, a series of benzothiazole derivatives was synthetized and assayed against promastigotes and intracellular amastigotes of <i>L</i>. <i>amazonensis</i>, as well as the toxicity on macrophages. In addition, studies about the mechanism of action were also performed. Among the synthesized molecules, the substitution at position 4 of the aromatic ring appears to be critical for activity. The best compound exhibited IC<sub>50</sub> values of 28.86 and 7.70 μM, against promastigotes and amastigotes of <i>L</i>. <i>amazonensis</i>, respectively, being more active than miltefosine, used as reference drug. The in silico analysis of physicochemical and pharmacokinetic (ADMET) properties of this compound suggested a good profile of oral bioavailability and safety. In conclusion, the strategy of using benzothiazole nucleous in the search for new antileishmanial agents was advantageous and preliminar data provide information about the mechanism of action as well as in silico parameters suggest a good profile for preclinical studies.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141629578","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Neuroinflammation is suggested as one of the potential links between CS-induced neuronal dysfunction. Cigarette smoke (CS) is one of the significant contributors of neuroinflammation, consequently leading to cognitive impairment and neurodegeneration. Microglia are the key resident macrophage cells in the brain with cell surface TLR4 receptor for responding to various stress signals. The CS constituents promote inflammation and oxidative stress in microglia leading to cytotoxicity through the TLR4-MK2 axis. However, the role of MK2 kinase in CS-induced microglial inflammation is not yet clearly understood. Therefore, we have used an MK2 inhibitor, PF-3644022 to study modulation of CS-extract induced oxidative and inflammatory signaling in a mouse microglial cell line, Furthermore, we also evaluated the enzymatic activity of acetylcholinesterase (AChE) on a direct exposure of enzyme with CS. CS exposure led to microglial cytotoxicity and enhanced the level of oxidative stress and proinflammatory cytokine release by microglial cells. The microglial cells pretreated with MK2 inhibitor, PF-3644022 significantly reduced the levels of oxidative stress markers, proinflammatory markers, and improved the level of antioxidant proteins in these cells. In addition, direct exposure of CS showed reduction in the enzymatic activity of AChE.
{"title":"MK2 inhibitor PF-3644022 shows protective effect in mouse microglial N9 cell line induced with cigarette smoke extract","authors":"Shikha Asthana, Shivam Kumar Pandey, Avtar Singh Gautam, Rakesh Kumar Singh","doi":"10.1111/cbdd.14592","DOIUrl":"10.1111/cbdd.14592","url":null,"abstract":"<p>Neuroinflammation is suggested as one of the potential links between CS-induced neuronal dysfunction. Cigarette smoke (CS) is one of the significant contributors of neuroinflammation, consequently leading to cognitive impairment and neurodegeneration. Microglia are the key resident macrophage cells in the brain with cell surface TLR4 receptor for responding to various stress signals. The CS constituents promote inflammation and oxidative stress in microglia leading to cytotoxicity through the TLR4-MK2 axis. However, the role of MK2 kinase in CS-induced microglial inflammation is not yet clearly understood. Therefore, we have used an MK2 inhibitor, PF-3644022 to study modulation of CS-extract induced oxidative and inflammatory signaling in a mouse microglial cell line, Furthermore, we also evaluated the enzymatic activity of acetylcholinesterase (AChE) on a direct exposure of enzyme with CS. CS exposure led to microglial cytotoxicity and enhanced the level of oxidative stress and proinflammatory cytokine release by microglial cells. The microglial cells pretreated with MK2 inhibitor, PF-3644022 significantly reduced the levels of oxidative stress markers, proinflammatory markers, and improved the level of antioxidant proteins in these cells. In addition, direct exposure of CS showed reduction in the enzymatic activity of AChE.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141629577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mei Qian Yau, Angeline J. Wan, Aaron S. H. Tiong, Yong Sheng Yiap, Jason S. E. Loo
Computational target fishing plays an important role in target identification, particularly in drug discovery campaigns utilizing phenotypic screening. Numerous approaches exist to predict potential targets for a given ligand, but true targets may be inconsistently ranked. More advanced simulation methods may provide benefit in such cases by reranking these initial predictions. We evaluated the ability of binding pose metadynamics to improve the predicted rankings for three diverse ligands and their six true targets. Initial predictions using pharmacophore mapping showed no true targets ranked in the top 50 and two targets each ranked within the 50–100, 100–150, and 250–300 ranges respectively. Following binding pose metadynamics, ranking of true targets improved for four out of the six targets and included the highest ranked predictions overall, while rankings deteriorated for two targets. The revised rankings predicted two true targets ranked within the top 50, and one target each within the 50–100, 100–150, 150–200, and 200–250 ranges respectively. The findings of this study demonstrate that binding pose metadynamics may be of benefit in refining initial predictions from structure-based target fishing algorithms, thereby improving the efficiency of the target identification process in drug discovery efforts.
{"title":"Leveraging binding pose metadynamics to optimise target fishing predictions for three diverse ligands and their true targets","authors":"Mei Qian Yau, Angeline J. Wan, Aaron S. H. Tiong, Yong Sheng Yiap, Jason S. E. Loo","doi":"10.1111/cbdd.14591","DOIUrl":"10.1111/cbdd.14591","url":null,"abstract":"<p>Computational target fishing plays an important role in target identification, particularly in drug discovery campaigns utilizing phenotypic screening. Numerous approaches exist to predict potential targets for a given ligand, but true targets may be inconsistently ranked. More advanced simulation methods may provide benefit in such cases by reranking these initial predictions. We evaluated the ability of binding pose metadynamics to improve the predicted rankings for three diverse ligands and their six true targets. Initial predictions using pharmacophore mapping showed no true targets ranked in the top 50 and two targets each ranked within the 50–100, 100–150, and 250–300 ranges respectively. Following binding pose metadynamics, ranking of true targets improved for four out of the six targets and included the highest ranked predictions overall, while rankings deteriorated for two targets. The revised rankings predicted two true targets ranked within the top 50, and one target each within the 50–100, 100–150, 150–200, and 200–250 ranges respectively. The findings of this study demonstrate that binding pose metadynamics may be of benefit in refining initial predictions from structure-based target fishing algorithms, thereby improving the efficiency of the target identification process in drug discovery efforts.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141621948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel, which is considered a highly validated target for pain perception. Repeated activation with agonists to desensitize receptors or use the antagonists can both exert analgesic effects. In this work, two series of novel phenylpiperazine derivatives were designed, synthesized, and evaluated for the in vitro receptor inhibitory activity and in vivo analgesic activity. Among them, L-21 containing sulfonylurea group was identified with potent TRPV1 antagonistic activity and analgesic activity in various pain models. At the same time, L-21 exhibited low risk of hyperthermia side effect. These results indicated that L-21 is a promising candidate for further development of novel TRPV1 antagonist to treat pain.
{"title":"Novel phenylpiperazine derivatives as potent transient receptor potential vanilloid 1 antagonists","authors":"Lina Jing, Chunxia Liu","doi":"10.1111/cbdd.14584","DOIUrl":"10.1111/cbdd.14584","url":null,"abstract":"<p>Transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel, which is considered a highly validated target for pain perception. Repeated activation with agonists to desensitize receptors or use the antagonists can both exert analgesic effects. In this work, two series of novel phenylpiperazine derivatives were designed, synthesized, and evaluated for the in vitro receptor inhibitory activity and in vivo analgesic activity. Among them, <b>L-21</b> containing sulfonylurea group was identified with potent TRPV1 antagonistic activity and analgesic activity in various pain models. At the same time, <b>L-21</b> exhibited low risk of hyperthermia side effect. These results indicated that <b>L-21</b> is a promising candidate for further development of novel TRPV1 antagonist to treat pain.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141602348","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Larissa R. S. P. Baliza, Túlio R. Freitas, Edward K. S. Gonçalves, Gabriel R. Antunes, Ana J. F. Souza, Julliane Yoneda, Caique Lopes Duarte, Silmara N. Andrade, Adriano de Paula Sabino, Fernando P. Varotti, Diego P. Sangi
N-heterocyclic compounds are important molecular scaffolds in the search for new drugs, since most drugs contain heterocyclic moieties in their molecular structure, and some of these classes of heterocycles are able to provide ligands for two or more biological targets. Ketene dithioacetals are important building blocks in organic synthesis and are widely used in the synthesis of N-heterocyclic compounds. In this work, we used double vinylic substitution reactions on ketene dithioacetals to synthesize a small library of heterocyclic derivatives and evaluated their cytotoxic activity in breast and ovarian cancer cells, identifying two benzoxazoles with good potency and selectivity. In silico predictions indicate that the two most active derivatives exhibit physicochemical properties within the range of drug-like compounds and showed potential to interact with HDAC8 and ERK1 cancer-related targets.
N 型杂环化合物是寻找新药物的重要分子支架,因为大多数药物的分子结构中都含有杂环分子,其中一些杂环类化合物能够为两个或多个生物靶标提供配体。烯酮二硫代乙醛是有机合成中的重要构件,被广泛用于合成 N-杂环化合物。在这项工作中,我们利用酮烯二硫代乙酸酯的双乙烯基取代反应合成了一个小型杂环衍生物库,并评估了它们在乳腺癌和卵巢癌细胞中的细胞毒性活性,确定了两种具有良好效力和选择性的苯并恶唑。硅学预测表明,这两种活性最强的衍生物的理化性质在类药物范围内,并显示出与 HDAC8 和 ERK1 癌症相关靶点相互作用的潜力。
{"title":"Synthesis and cytotoxic evaluation of heterocyclic compounds by vinylic substitution of ketene dithioacetals","authors":"Larissa R. S. P. Baliza, Túlio R. Freitas, Edward K. S. Gonçalves, Gabriel R. Antunes, Ana J. F. Souza, Julliane Yoneda, Caique Lopes Duarte, Silmara N. Andrade, Adriano de Paula Sabino, Fernando P. Varotti, Diego P. Sangi","doi":"10.1111/cbdd.14581","DOIUrl":"10.1111/cbdd.14581","url":null,"abstract":"<p><i>N</i>-heterocyclic compounds are important molecular scaffolds in the search for new drugs, since most drugs contain heterocyclic moieties in their molecular structure, and some of these classes of heterocycles are able to provide ligands for two or more biological targets. Ketene dithioacetals are important building blocks in organic synthesis and are widely used in the synthesis of <i>N</i>-heterocyclic compounds. In this work, we used double vinylic substitution reactions on ketene dithioacetals to synthesize a small library of heterocyclic derivatives and evaluated their cytotoxic activity in breast and ovarian cancer cells, identifying two benzoxazoles with good potency and selectivity. In silico predictions indicate that the two most active derivatives exhibit physicochemical properties within the range of drug-like compounds and showed potential to interact with HDAC8 and ERK1 cancer-related targets.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141602349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jiangfei Liu, Yaohui Ni, Keyun Zhou, Guanzhao Wu, Liangyong Hu, Tianyu Zhu, Defeng Xu, Hang Hu
In this work, a series of curcumin derivatives (1a–1h, 2a–2g, and 3a–3c) were synthesized for the suppression of castration-resistant prostate cancer cells. All synthesized compounds were characterized by 1H NMR, 13C NMR, HRMS, and melting point. The in vitro cytotoxicity study shows that compounds 1a, 1e, 1f, 1h, 2g, 3a, and 3c display similar or enhanced cytotoxicity against 22Rv1 and C4-2 cells as compared to ASC-J9, other synthesized compounds display reduced cytotoxicity against 22Rv1 and C4-2 cells as compared to ASC-J9. Molecular docking simulation was performed to study the binding affinity and probable binding modes of the synthesized compounds with androgen receptor. The results show that all synthesized compounds exhibit higher cdocker interaction energies as compared to ASC-J9. Compounds 1h, 2g, and 3c not only show strong cytotoxicity against 22Rv1 and C4-2 cells but also exhibit high binding affinity with androgen receptor. In androgen receptor suppression study, compounds 1f and 2g show similar androgen receptor suppression effect as compared to ASC-J9 on C4-2 cells, compound 3c displays significantly enhanced AR suppression effect as compared to ASC-J9, 1f and 2g. Compounds 1a, 1e, 1f, 1h, 2g, 3a and 3c prepared in this work have significant potential for castration-resistant prostate cancer therapy.
{"title":"Synthesis of curcumin derivatives targeting androgen receptor for castration-resistant prostate cancer therapy","authors":"Jiangfei Liu, Yaohui Ni, Keyun Zhou, Guanzhao Wu, Liangyong Hu, Tianyu Zhu, Defeng Xu, Hang Hu","doi":"10.1111/cbdd.14583","DOIUrl":"10.1111/cbdd.14583","url":null,"abstract":"<p>In this work, a series of curcumin derivatives (<b>1a–1h</b>, <b>2a–2g</b>, and <b>3a–3c</b>) were synthesized for the suppression of castration-resistant prostate cancer cells. All synthesized compounds were characterized by <sup>1</sup>H NMR, <sup>13</sup>C NMR, HRMS, and melting point. The in vitro cytotoxicity study shows that compounds <b>1a</b>, <b>1e</b>, <b>1f</b>, <b>1h</b>, <b>2g</b>, <b>3a</b>, and <b>3c</b> display similar or enhanced cytotoxicity against 22Rv1 and C4-2 cells as compared to ASC-J9, other synthesized compounds display reduced cytotoxicity against 22Rv1 and C4-2 cells as compared to ASC-J9. Molecular docking simulation was performed to study the binding affinity and probable binding modes of the synthesized compounds with androgen receptor. The results show that all synthesized compounds exhibit higher cdocker interaction energies as compared to ASC-J9. Compounds <b>1h</b>, <b>2g</b>, and <b>3c</b> not only show strong cytotoxicity against 22Rv1 and C4-2 cells but also exhibit high binding affinity with androgen receptor. In androgen receptor suppression study, compounds <b>1f</b> and <b>2g</b> show similar androgen receptor suppression effect as compared to ASC-J9 on C4-2 cells, compound <b>3c</b> displays significantly enhanced AR suppression effect as compared to ASC-J9, <b>1f</b> and <b>2g</b>. Compounds <b>1a</b>, <b>1e</b>, <b>1f</b>, <b>1h</b>, <b>2g</b>, <b>3a</b> and <b>3c</b> prepared in this work have significant potential for castration-resistant prostate cancer therapy.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141592428","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Zhang K, Li JY, Li K. Silencing PCMT1 enhances the sensitivity of breast cancer cells to paclitaxel through the PI3K/Akt/STMN1 pathway. Chem Biol Drug Des. 2024 Jun;103(6):e14559. doi: 10.1111/cbdd.14559. PMID: 38853025.
In page 1 of Author Information section, the text “Correspondence Kai Li, Department of Oncology, Renmin Hospital, Hubei University of Medicine, Shiyan 442000, Hubei, China. Email: [email protected]” was incorrect. This should have read: “Correspondence Kai Li, Department of Pathology, Renmin Hospital, Hubei University of Medicine, Shiyan 442000, Hubei, China. Email: [email protected].”
We apologize for this error.
Zhang K, Li JY, Li K. Silencing PCMT1 enhanced the sensitivity of breast cancer cells to paclitaxel through the PI3K/Akt/STMN1 pathway.Chem Biol Drug Des.2024 Jun;103(6):e14559. Doi: 10.1111/cbdd.14559.PMID:38853025.第1页 "作者信息 "中的 "通讯作者:湖北十堰442000 湖北医药学院附属人民医院肿瘤科 李凯"。电子邮箱:[email protected]"有误:[email protected]"有误。应改为"Correspondence Kai Li, Department of Pathology, Renmin Hospital, Hubei University of Medicine, Shiyan 442000, Hubei, China.电子邮箱:[email protected]:[email protected]。"我们对此错误深表歉意。
{"title":"Correction to Silencing PCMT1 enhances the sensitivity of breast cancer cells to paclitaxel through the PI3K/Akt/STMN1 pathway","authors":"","doi":"10.1111/cbdd.14577","DOIUrl":"10.1111/cbdd.14577","url":null,"abstract":"<p>Zhang K, Li JY, Li K. Silencing PCMT1 enhances the sensitivity of breast cancer cells to paclitaxel through the PI3K/Akt/STMN1 pathway. <i>Chem Biol Drug Des</i>. 2024 Jun;103(6):e14559. doi: 10.1111/cbdd.14559. PMID: 38853025.</p><p>In page 1 of Author Information section, the text “Correspondence Kai Li, Department of Oncology, Renmin Hospital, Hubei University of Medicine, Shiyan 442000, Hubei, China. Email: <span>[email protected]</span>” was incorrect. This should have read: “Correspondence Kai Li, Department of Pathology, Renmin Hospital, Hubei University of Medicine, Shiyan 442000, Hubei, China. Email: <span>[email protected]</span>.”</p><p>We apologize for this error.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cbdd.14577","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141565371","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Intestinal absorption of compounds is significant in drug research and development. To evaluate this efficiently, a method combining mathematical modeling and molecular simulation was proposed, from the perspective of molecular structure. Based on the quantitative structure–property relationship study, the model between molecular structure and their apparent permeability coefficients was successfully constructed and verified, predicting intestinal absorption of drugs and interpreting decisive structural factors, such as AlogP98, Hydrogen bond donor and Ellipsoidal volume. The molecules with strong lipophilicity, less hydrogen bond donors and receptors, and small molecular volume are more easily absorbed. Then, the molecular dynamics simulation and molecular docking were utilized to study the mechanism of differences in intestinal absorption of drugs and investigate the role of molecular structure. Results indicated that molecules with strong lipophilicity and small volume interacted with the membrane at a lower energy and were easier to penetrate the membrane. Likewise, they had weaker interaction with P-glycoprotein and were easier to escape from it and harder to export from the body. More in, less out, is the main reason these molecules absorb well.
化合物的肠道吸收在药物研发中意义重大。为了有效评估这一问题,研究人员从分子结构的角度出发,提出了一种数学建模与分子模拟相结合的方法。在定量结构-性质关系研究的基础上,成功构建并验证了分子结构与表观渗透系数之间的模型,预测了药物的肠道吸收,并解释了AlogP98、氢键供体和椭圆体体积等决定性结构因素。亲脂性强、氢键供体和受体少、分子体积小的分子更容易被吸收。然后,利用分子动力学模拟和分子对接研究了药物在肠道吸收的差异机理,并探讨了分子结构的作用。结果表明,亲脂性强、体积小的分子与膜的相互作用能量较低,更容易穿透膜。同样,它们与 P 糖蛋白的相互作用较弱,更容易从 P 糖蛋白中逃脱,也更难从体内排出。多进少出是这些分子吸收好的主要原因。
{"title":"A hybrid evaluation of the intestinal absorption performance of compounds from molecular structure","authors":"Mengke Sheng, Lina Ma, Zhixun Li, Xinhui Peng, Shuai Cen, Minfang Feng, Yuting Tian, Xingxing Dai, Xinyuan Shi","doi":"10.1111/cbdd.14576","DOIUrl":"10.1111/cbdd.14576","url":null,"abstract":"<p>Intestinal absorption of compounds is significant in drug research and development. To evaluate this efficiently, a method combining mathematical modeling and molecular simulation was proposed, from the perspective of molecular structure. Based on the quantitative structure–property relationship study, the model between molecular structure and their apparent permeability coefficients was successfully constructed and verified, predicting intestinal absorption of drugs and interpreting decisive structural factors, such as AlogP98, Hydrogen bond donor and Ellipsoidal volume. The molecules with strong lipophilicity, less hydrogen bond donors and receptors, and small molecular volume are more easily absorbed. Then, the molecular dynamics simulation and molecular docking were utilized to study the mechanism of differences in intestinal absorption of drugs and investigate the role of molecular structure. Results indicated that molecules with strong lipophilicity and small volume interacted with the membrane at a lower energy and were easier to penetrate the membrane. Likewise, they had weaker interaction with P-glycoprotein and were easier to escape from it and harder to export from the body. More in, less out, is the main reason these molecules absorb well.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141539042","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yinhui Qin, Yuetai Teng, Yan Yang, Zhenkun Mao, Shengyu Zhao, Na Zhang, Xu Li, Weihong Niu
Infectious diseases have been jeopardized problem that threaten public health over a long period of time. The growing prevalence of drug-resistant pathogens and infectious cases have led to a decrease in the number of effective antibiotics, which highlights the urgent need for the development of new antibacterial agents. Serine acetyltransferase (SAT), also known as CysE in certain bacterial species, and O-acetylserine sulfhydrylase (OASS), also known as CysK in select bacteria, are indispensable enzymes within the cysteine biosynthesis pathway of various pathogenic microorganisms. These enzymes play a crucial role in the survival of these pathogens, making SAT and OASS promising targets for the development of novel anti-infective agents. In this comprehensive review, we present an introduction to the structure and function of SAT and OASS, along with an overview of existing inhibitors for SAT and OASS as potential antibacterial agents. Our primary focus is on elucidating the inhibitory activities, structure–activity relationships, and mechanisms of action of these inhibitors. Through this exploration, we aim to provide insights into promising strategies and prospects in the development of antibacterial agents that target these essential enzymes.
长期以来,传染病一直是威胁公众健康的棘手问题。耐药性病原体和传染病病例的日益增多导致有效抗生素的数量减少,这突出表明迫切需要开发新的抗菌剂。丝氨酸乙酰转移酶(SAT)(在某些细菌物种中也称为 CysE)和 O-乙酰丝氨酸巯基酶(OASS)(在某些细菌中也称为 CysK)是各种病原微生物半胱氨酸生物合成途径中不可或缺的酶。这些酶对这些病原体的生存起着至关重要的作用,因此 SAT 和 OASS 是开发新型抗感染药物的理想靶标。在这篇综述中,我们介绍了 SAT 和 OASS 的结构和功能,并概述了作为潜在抗菌剂的现有 SAT 和 OASS 抑制剂。我们的主要重点是阐明这些抑制剂的抑制活性、结构-活性关系和作用机制。通过这一探索,我们旨在为针对这些重要酶的抗菌剂的开发提供有前途的策略和前景。
{"title":"Advancements in inhibitors of crucial enzymes in the cysteine biosynthetic pathway: Serine acetyltransferase and O-acetylserine sulfhydrylase","authors":"Yinhui Qin, Yuetai Teng, Yan Yang, Zhenkun Mao, Shengyu Zhao, Na Zhang, Xu Li, Weihong Niu","doi":"10.1111/cbdd.14573","DOIUrl":"10.1111/cbdd.14573","url":null,"abstract":"<p>Infectious diseases have been jeopardized problem that threaten public health over a long period of time. The growing prevalence of drug-resistant pathogens and infectious cases have led to a decrease in the number of effective antibiotics, which highlights the urgent need for the development of new antibacterial agents. Serine acetyltransferase (SAT), also known as CysE in certain bacterial species, and <i>O</i>-acetylserine sulfhydrylase (OASS), also known as CysK in select bacteria, are indispensable enzymes within the cysteine biosynthesis pathway of various pathogenic microorganisms. These enzymes play a crucial role in the survival of these pathogens, making SAT and OASS promising targets for the development of novel anti-infective agents. In this comprehensive review, we present an introduction to the structure and function of SAT and OASS, along with an overview of existing inhibitors for SAT and OASS as potential antibacterial agents. Our primary focus is on elucidating the inhibitory activities, structure–activity relationships, and mechanisms of action of these inhibitors. Through this exploration, we aim to provide insights into promising strategies and prospects in the development of antibacterial agents that target these essential enzymes.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141536236","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}