{"title":"\"针对 PI3K/AKT/mTOR 通路的乳腺癌治疗的新型羟基脲脂质药物共轭物的分子内设计与开发\"。","authors":"Saranya Dharmaraj, Akey Krishna Swaroop, Mariappan Esakkimuthukumar, Preeya Negi, Selvaraj Jubie","doi":"10.1055/a-2213-8457","DOIUrl":null,"url":null,"abstract":"<p><p>Hydroxyurea (HU) has shown promise in breast cancer treatment, but its hydrophilic nature limits its efficacy. Therefore, conjugating HU with lipids could increase its liphophilicity and improve its cellular uptake, leading to increased efficacy and reduced toxicity. The PI3K/Akt/mTOR pathway is an attractive therapeutic target in cancer not only because it is the second most frequently altered pathway after p53, but also because it serves as a convergence point for many stimuli. The aim of this study is to design and develop novel hydroxyurea lipid drug conjugates for breast cancer therapy targeting the PI3K/Akt/mTOR pathway using <i>in-silico</i> and <i>in-vitro</i> approaches. The conjugates are designed and docked with the proteins selected for each target like PI3K (PDB ID;2JDO), AKT (PDB ID;3APF), mTOR (PDB ID;4JST). The conjugates with higher docking scores are taken for ADME studies and molecular dynamics. Stearic, lauric, palmitic, myristic and linolenic acids have been used for the conjugation. The conjugates are synthesized and characterized. The HLB calculation and partition coefficient are carried out to find the improvement in liphophilicity of the conjugates compared to hydroxyurea. Finally, the <i>in-vitro</i> cytotoxicity studies are performed with MCF -7 cell lines and the compound HU-MA (hydroxyurea with myristic acid) with low IC<sub>50</sub> is considered as the compound having good activity with compound code. These conjugates have been shown to have improved drug solubility and better cellular uptake compared to free hydroxyurea, which can increase drug efficacy.</p>","PeriodicalId":11451,"journal":{"name":"Drug Research","volume":"74 1","pages":"32-41"},"PeriodicalIF":1.7000,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"\\\"In-silico Design and Development of Novel Hydroxyurea Lipid Drug Conjugates for Breast Cancer Therapy Targeting PI3K/AKT/mTOR Pathway\\\".\",\"authors\":\"Saranya Dharmaraj, Akey Krishna Swaroop, Mariappan Esakkimuthukumar, Preeya Negi, Selvaraj Jubie\",\"doi\":\"10.1055/a-2213-8457\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Hydroxyurea (HU) has shown promise in breast cancer treatment, but its hydrophilic nature limits its efficacy. Therefore, conjugating HU with lipids could increase its liphophilicity and improve its cellular uptake, leading to increased efficacy and reduced toxicity. The PI3K/Akt/mTOR pathway is an attractive therapeutic target in cancer not only because it is the second most frequently altered pathway after p53, but also because it serves as a convergence point for many stimuli. The aim of this study is to design and develop novel hydroxyurea lipid drug conjugates for breast cancer therapy targeting the PI3K/Akt/mTOR pathway using <i>in-silico</i> and <i>in-vitro</i> approaches. The conjugates are designed and docked with the proteins selected for each target like PI3K (PDB ID;2JDO), AKT (PDB ID;3APF), mTOR (PDB ID;4JST). The conjugates with higher docking scores are taken for ADME studies and molecular dynamics. Stearic, lauric, palmitic, myristic and linolenic acids have been used for the conjugation. The conjugates are synthesized and characterized. The HLB calculation and partition coefficient are carried out to find the improvement in liphophilicity of the conjugates compared to hydroxyurea. Finally, the <i>in-vitro</i> cytotoxicity studies are performed with MCF -7 cell lines and the compound HU-MA (hydroxyurea with myristic acid) with low IC<sub>50</sub> is considered as the compound having good activity with compound code. These conjugates have been shown to have improved drug solubility and better cellular uptake compared to free hydroxyurea, which can increase drug efficacy.</p>\",\"PeriodicalId\":11451,\"journal\":{\"name\":\"Drug Research\",\"volume\":\"74 1\",\"pages\":\"32-41\"},\"PeriodicalIF\":1.7000,\"publicationDate\":\"2024-01-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Drug Research\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1055/a-2213-8457\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/1/11 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q3\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Drug Research","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1055/a-2213-8457","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/1/11 0:00:00","PubModel":"Epub","JCR":"Q3","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
"In-silico Design and Development of Novel Hydroxyurea Lipid Drug Conjugates for Breast Cancer Therapy Targeting PI3K/AKT/mTOR Pathway".
Hydroxyurea (HU) has shown promise in breast cancer treatment, but its hydrophilic nature limits its efficacy. Therefore, conjugating HU with lipids could increase its liphophilicity and improve its cellular uptake, leading to increased efficacy and reduced toxicity. The PI3K/Akt/mTOR pathway is an attractive therapeutic target in cancer not only because it is the second most frequently altered pathway after p53, but also because it serves as a convergence point for many stimuli. The aim of this study is to design and develop novel hydroxyurea lipid drug conjugates for breast cancer therapy targeting the PI3K/Akt/mTOR pathway using in-silico and in-vitro approaches. The conjugates are designed and docked with the proteins selected for each target like PI3K (PDB ID;2JDO), AKT (PDB ID;3APF), mTOR (PDB ID;4JST). The conjugates with higher docking scores are taken for ADME studies and molecular dynamics. Stearic, lauric, palmitic, myristic and linolenic acids have been used for the conjugation. The conjugates are synthesized and characterized. The HLB calculation and partition coefficient are carried out to find the improvement in liphophilicity of the conjugates compared to hydroxyurea. Finally, the in-vitro cytotoxicity studies are performed with MCF -7 cell lines and the compound HU-MA (hydroxyurea with myristic acid) with low IC50 is considered as the compound having good activity with compound code. These conjugates have been shown to have improved drug solubility and better cellular uptake compared to free hydroxyurea, which can increase drug efficacy.
期刊介绍:
Drug Research (formerly Arzneimittelforschung) is an international peer-reviewed journal with expedited processing times presenting the very latest research results related to novel and established drug molecules and the evaluation of new drug development. A key focus of the publication is translational medicine and the application of biological discoveries in the development of drugs for use in the clinical environment. Articles and experimental data from across the field of drug research address not only the issue of drug discovery, but also the mathematical and statistical methods for evaluating results from industrial investigations and clinical trials. Publishing twelve times a year, Drug Research includes original research articles as well as reviews, commentaries and short communications in the following areas: analytics applied to clinical trials chemistry and biochemistry clinical and experimental pharmacology drug interactions efficacy testing pharmacodynamics pharmacokinetics teratology toxicology.