Humaira Zafar, Rabbia Anis, Sana Hafeez, Atia-Tul Wahab, Maria Aqeel Khan, Fatima Zehra Basha, Innokentiy Maslennikov, Muhammad Iqbal Choudhary
{"title":"通过硅学和体外研究鉴定非甾体类芳香化酶抑制剂","authors":"Humaira Zafar, Rabbia Anis, Sana Hafeez, Atia-Tul Wahab, Maria Aqeel Khan, Fatima Zehra Basha, Innokentiy Maslennikov, Muhammad Iqbal Choudhary","doi":"10.2174/1573406419666230330082426","DOIUrl":null,"url":null,"abstract":"<p><strong>Introduction: </strong>Breast cancer is the most common cancer affecting women worldwide,\nincluding Pakistan. More than half of breast cancer patients have hormone-dependent breast cancer,\nwhich is developed due to the over-production of estrogen (the main hormone in breast cancer).</p><p><strong>Method: </strong>The biosynthesis of estrogen is catalyzed by the aromatase enzyme, which thus serves as a\ntarget for the treatment of breast cancer. During the current study, biochemical, computational, and\nSTD-NMR methods were employed to identify new aromatase inhibitors. A series of phenyl-3-\nbutene-2-one derivatives 1-9 were synthesized and evaluated for human placental aromatase inhibitory activity. Among them, four compounds 2, 3, 4, and 8 showed a moderate to weak inhibitory activity (IC50 = 22.6 - 47.9 µM), as compared to standard aromatase inhibitory drugs, letrozole (IC50 =\n0.0147 ± 1.45 µM), anastrozole (IC50 = 0.0094 ± 0.91 µM), and exemestane (IC50 = 0.2 ± 0.032 µM).\nKinetic studies on two moderate inhibitors, 4 and 8, revealed a competitive- and mixed-type of inhibition, respectively.</p><p><strong>Result: </strong>Docking studies on all active compounds indicated their binding adjacent to the heme group\nand interaction with Met374, a critical residue of aromatase. STD-NMR further highlighted the interactions of these ligands with the aromatase enzyme.</p><p><strong>Conclusion: </strong>STD-NMR-based epitope mapping indicated close proximity of the alkyl chain followed by an aromatic ring with the receptor (aromatase). These compounds were also found to be\nnon-cytotoxic against human fibroblast cells (BJ cells). Thus, the current study has identified new\naromatase inhibitors (compounds 4, and 8) for further pre-clinical and clinical research.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":1.9000,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Identification of Non-steroidal Aromatase Inhibitors via In silico and In vitro Studies\",\"authors\":\"Humaira Zafar, Rabbia Anis, Sana Hafeez, Atia-Tul Wahab, Maria Aqeel Khan, Fatima Zehra Basha, Innokentiy Maslennikov, Muhammad Iqbal Choudhary\",\"doi\":\"10.2174/1573406419666230330082426\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Introduction: </strong>Breast cancer is the most common cancer affecting women worldwide,\\nincluding Pakistan. More than half of breast cancer patients have hormone-dependent breast cancer,\\nwhich is developed due to the over-production of estrogen (the main hormone in breast cancer).</p><p><strong>Method: </strong>The biosynthesis of estrogen is catalyzed by the aromatase enzyme, which thus serves as a\\ntarget for the treatment of breast cancer. During the current study, biochemical, computational, and\\nSTD-NMR methods were employed to identify new aromatase inhibitors. A series of phenyl-3-\\nbutene-2-one derivatives 1-9 were synthesized and evaluated for human placental aromatase inhibitory activity. Among them, four compounds 2, 3, 4, and 8 showed a moderate to weak inhibitory activity (IC50 = 22.6 - 47.9 µM), as compared to standard aromatase inhibitory drugs, letrozole (IC50 =\\n0.0147 ± 1.45 µM), anastrozole (IC50 = 0.0094 ± 0.91 µM), and exemestane (IC50 = 0.2 ± 0.032 µM).\\nKinetic studies on two moderate inhibitors, 4 and 8, revealed a competitive- and mixed-type of inhibition, respectively.</p><p><strong>Result: </strong>Docking studies on all active compounds indicated their binding adjacent to the heme group\\nand interaction with Met374, a critical residue of aromatase. STD-NMR further highlighted the interactions of these ligands with the aromatase enzyme.</p><p><strong>Conclusion: </strong>STD-NMR-based epitope mapping indicated close proximity of the alkyl chain followed by an aromatic ring with the receptor (aromatase). These compounds were also found to be\\nnon-cytotoxic against human fibroblast cells (BJ cells). Thus, the current study has identified new\\naromatase inhibitors (compounds 4, and 8) for further pre-clinical and clinical research.</p>\",\"PeriodicalId\":18382,\"journal\":{\"name\":\"Medicinal Chemistry\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":1.9000,\"publicationDate\":\"2023-01-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Medicinal Chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.2174/1573406419666230330082426\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.2174/1573406419666230330082426","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Identification of Non-steroidal Aromatase Inhibitors via In silico and In vitro Studies
Introduction: Breast cancer is the most common cancer affecting women worldwide,
including Pakistan. More than half of breast cancer patients have hormone-dependent breast cancer,
which is developed due to the over-production of estrogen (the main hormone in breast cancer).
Method: The biosynthesis of estrogen is catalyzed by the aromatase enzyme, which thus serves as a
target for the treatment of breast cancer. During the current study, biochemical, computational, and
STD-NMR methods were employed to identify new aromatase inhibitors. A series of phenyl-3-
butene-2-one derivatives 1-9 were synthesized and evaluated for human placental aromatase inhibitory activity. Among them, four compounds 2, 3, 4, and 8 showed a moderate to weak inhibitory activity (IC50 = 22.6 - 47.9 µM), as compared to standard aromatase inhibitory drugs, letrozole (IC50 =
0.0147 ± 1.45 µM), anastrozole (IC50 = 0.0094 ± 0.91 µM), and exemestane (IC50 = 0.2 ± 0.032 µM).
Kinetic studies on two moderate inhibitors, 4 and 8, revealed a competitive- and mixed-type of inhibition, respectively.
Result: Docking studies on all active compounds indicated their binding adjacent to the heme group
and interaction with Met374, a critical residue of aromatase. STD-NMR further highlighted the interactions of these ligands with the aromatase enzyme.
Conclusion: STD-NMR-based epitope mapping indicated close proximity of the alkyl chain followed by an aromatic ring with the receptor (aromatase). These compounds were also found to be
non-cytotoxic against human fibroblast cells (BJ cells). Thus, the current study has identified new
aromatase inhibitors (compounds 4, and 8) for further pre-clinical and clinical research.
期刊介绍:
Aims & Scope
Medicinal Chemistry a peer-reviewed journal, aims to cover all the latest outstanding developments in medicinal chemistry and rational drug design. The journal publishes original research, mini-review articles and guest edited thematic issues covering recent research and developments in the field. Articles are published rapidly by taking full advantage of Internet technology for both the submission and peer review of manuscripts. Medicinal Chemistry is an essential journal for all involved in drug design and discovery.