Highlighting the Therapeutic Potential of an Underexplored Target: Human Dihydroorotate Dehydrogenase in Cancer, Rheumatoid Arthritis and Sclerosis.

IF 2.9 4区 医学 Q3 CHEMISTRY, MEDICINAL
Shubham Dash, Rupali Verma, Shorya Thakur, Gurvinder Singh, Charanjit Kaur
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引用次数: 0

Abstract

Introduction: The dihydroorotate dehydrogenase (DHODH) enzyme plays a crucial role in the de novo pyrimidine biosynthesis pathway, catalysing the conversion of dihydroorotate to orotate in the cells. This pathway is important for the synthesis of nucleic acids and vital molecules essential for homeostasis, cellular functioning, and survival. So, targeting this enzyme can be an effective approach for the treatment of cancer, arthritis, malaria, viral or microbial infections, and other autoimmune diseases.

Methods: In this review, we have highlighted the therapeutic implications of DHODH inhibition in cancer, rheumatoid arthritis and multiple sclerosis through an extensive literature survey from various scientific databases like PubMed, Google Scholar, Science Direct, Embase, clinical trials. gov.in, Google Patents, etc. Results: We have tried to identify the pharmacophores from synthetic, phytochemical, and microbial origins, effective as DHODH inhibitors. The effect of structural changes on activity has been summarised, providing insights into the efficacy and mechanisms of these inhibitors at the molecular level. Furthermore, this review also presents a comprehensive analysis of clinical trials and patents related to DHODH inhibition to extract the valuable information to be used for clinical drug development in cancer, rheumatoid arthritis, and multiple sclerosis.

Conclusion: By integrating data from synthetic, plant, and microbial sources, along with clinical trial and patent outcomes, this review highlights the diverse role of DHODH. Its inhibition offers a more targeted approach to reduce the proliferation of rapidly dividing cells while sparing normal cells, modulating specific immune responses. But, limiting understanding of resistance mechanisms and potential for toxicity are the current challenges. It offers a roadmap for future research and drug discovery endeavours focused on harnessing the beneficial potential of DHODH inhibition, including the development of novel inhibitors with improved selectivity and pharmacokinetics across a wide array of pathological conditions.

强调一个未开发靶点的治疗潜力:人类二氢乙酸脱氢酶在癌症、类风湿关节炎和硬化症中的作用。
简介:二氢羊角酸脱氢酶(dihydroorotate dehydrogenase, DHODH)在从头合成嘧啶的生物途径中起着至关重要的作用,在细胞中催化二氢羊角酸转化为羊角酸。这一途径对于核酸和维持体内平衡、细胞功能和生存所必需的重要分子的合成至关重要。因此,靶向这种酶可能是治疗癌症、关节炎、疟疾、病毒或微生物感染以及其他自身免疫性疾病的有效方法。方法:在本综述中,我们通过对PubMed、谷歌Scholar、Science Direct、Embase、临床试验等各种科学数据库的广泛文献调查,强调了DHODH抑制在癌症、类风湿性关节炎和多发性硬化症中的治疗意义。政府,谷歌专利等。结果:我们试图从合成、植物化学和微生物来源中鉴定出有效的DHODH抑制剂。对结构变化对活性的影响进行了总结,提供了这些抑制剂在分子水平上的功效和机制的见解。此外,本文还对DHODH抑制相关的临床试验和专利进行了全面分析,以提取有价值的信息,用于癌症、类风湿关节炎和多发性硬化症的临床药物开发。结论:通过整合来自合成、植物和微生物来源的数据,以及临床试验和专利结果,本综述强调了DHODH的多种作用。它的抑制提供了一种更有针对性的方法来减少快速分裂细胞的增殖,同时保留正常细胞,调节特异性免疫反应。但是,限制对耐药机制和潜在毒性的理解是当前的挑战。它为未来的研究和药物发现工作提供了路线图,重点是利用DHODH抑制的有益潜力,包括开发具有改善选择性和药代动力学的新型抑制剂,跨越广泛的病理条件。
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来源期刊
CiteScore
6.40
自引率
2.90%
发文量
186
审稿时长
3-8 weeks
期刊介绍: Current Topics in Medicinal Chemistry is a forum for the review of areas of keen and topical interest to medicinal chemists and others in the allied disciplines. Each issue is solely devoted to a specific topic, containing six to nine reviews, which provide the reader a comprehensive survey of that area. A Guest Editor who is an expert in the topic under review, will assemble each issue. The scope of Current Topics in Medicinal Chemistry will cover all areas of medicinal chemistry, including current developments in rational drug design, synthetic chemistry, bioorganic chemistry, high-throughput screening, combinatorial chemistry, compound diversity measurements, drug absorption, drug distribution, metabolism, new and emerging drug targets, natural products, pharmacogenomics, and structure-activity relationships. Medicinal chemistry is a rapidly maturing discipline. The study of how structure and function are related is absolutely essential to understanding the molecular basis of life. Current Topics in Medicinal Chemistry aims to contribute to the growth of scientific knowledge and insight, and facilitate the discovery and development of new therapeutic agents to treat debilitating human disorders. The journal is essential for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important advances.
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