Abstract
Dihydroorotate dehydrogenase (DHODH) is a flavin-dependent mitochondrial enzyme that catalyzes fourth reaction of pyrimidine de-novo synthesis. Pyrimidine bases are essential for cellular metabolism and cell growth, and are considered as important precursors used in DNA (thymine and cytosine), RNA (uracil and cytosine), glycoproteins and phospholipids biosynthesis. The significance of pyrimidines biosynthesis in DNA and RNA makes them ideal targets for pharmacological intervention. Inhibitors of DHODH have proven efficacy for the treatment of malaria, autoimmune diseases, cancer, rheumatoid arthritis and psoriasis. Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) represents an important target for the treatment of malaria. Many of the clinically relevant anti-tumor and immunosuppressive drugs target human dihydroorotate dehydrogenase (hDHODH), and the two most promising drugs of such kinds are brequinar (antitumor and immunosuppressive) and leflunomide (immunosuppressive). X-ray crystal structures of DHODH in complex with inhibitors reveal common binding region shared by each inhibitor. A number of compounds are identified by high-throughput screening (HTS) of chemical libraries and structure-based computational approaches as selective DHODH inhibitors. Based upon the understanding of molecular interaction of DHODH inhibitors with binding site, some of the common structural features are identified like ability of compounds to interact with ubiquinone (CoQ) binding site and substituents linked to a variety of heterocyclic and heteroaromatic rings responsible for H-bonding with binding site. These findings provide new approaches to design DHODH inhibitors and highlights DHODH as a target for chemotherapeutics. This review is mainly focused on the recent developments in the medicinal chemistry and therapeutic potential of DHODH inhibitors as a target for drug discovery.
Keywords: Dihydroorotate dehydrogenase (DHODH), pyrimidines biosynthesis, DHODH inhibitors, cancer, arthritis, malaria, flavin-dependent, mitochondrial enzyme, pyrimidine, Plasmodium falciparum, leflunomide, brequinar
Mini-Reviews in Medicinal Chemistry
Title: Recent Developments in the Medicinal Chemistry and Therapeutic Potential of Dihydroorotate Dehydrogenase (DHODH) Inhibitors
Volume: 11 Issue: 12
Author(s): V. K. Vyas and M. Ghate
Affiliation:
Keywords: Dihydroorotate dehydrogenase (DHODH), pyrimidines biosynthesis, DHODH inhibitors, cancer, arthritis, malaria, flavin-dependent, mitochondrial enzyme, pyrimidine, Plasmodium falciparum, leflunomide, brequinar
Abstract: Dihydroorotate dehydrogenase (DHODH) is a flavin-dependent mitochondrial enzyme that catalyzes fourth reaction of pyrimidine de-novo synthesis. Pyrimidine bases are essential for cellular metabolism and cell growth, and are considered as important precursors used in DNA (thymine and cytosine), RNA (uracil and cytosine), glycoproteins and phospholipids biosynthesis. The significance of pyrimidines biosynthesis in DNA and RNA makes them ideal targets for pharmacological intervention. Inhibitors of DHODH have proven efficacy for the treatment of malaria, autoimmune diseases, cancer, rheumatoid arthritis and psoriasis. Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) represents an important target for the treatment of malaria. Many of the clinically relevant anti-tumor and immunosuppressive drugs target human dihydroorotate dehydrogenase (hDHODH), and the two most promising drugs of such kinds are brequinar (antitumor and immunosuppressive) and leflunomide (immunosuppressive). X-ray crystal structures of DHODH in complex with inhibitors reveal common binding region shared by each inhibitor. A number of compounds are identified by high-throughput screening (HTS) of chemical libraries and structure-based computational approaches as selective DHODH inhibitors. Based upon the understanding of molecular interaction of DHODH inhibitors with binding site, some of the common structural features are identified like ability of compounds to interact with ubiquinone (CoQ) binding site and substituents linked to a variety of heterocyclic and heteroaromatic rings responsible for H-bonding with binding site. These findings provide new approaches to design DHODH inhibitors and highlights DHODH as a target for chemotherapeutics. This review is mainly focused on the recent developments in the medicinal chemistry and therapeutic potential of DHODH inhibitors as a target for drug discovery.
Export Options
About this article
Cite this article as:
K. Vyas V. and Ghate M., Recent Developments in the Medicinal Chemistry and Therapeutic Potential of Dihydroorotate Dehydrogenase (DHODH) Inhibitors, Mini-Reviews in Medicinal Chemistry 2011; 11 (12) . https://dx.doi.org/10.2174/138955711797247707
DOI https://dx.doi.org/10.2174/138955711797247707 |
Print ISSN 1389-5575 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5607 |
Call for Papers in Thematic Issues
Bioprospecting of Natural Products as Sources of New Multitarget Therapies
According to the Convention on Biological Diversity, bioprospecting is the exploration of biodiversity and indigenous knowledge to develop commercially valuable products for pharmaceutical and other applications. Bioprospecting involves searching for useful organic compounds in plants, fungi, marine organisms, and microorganisms. Natural products traditionally constituted the primary source of more than ...read more
Computational Frontiers in Medicinal Chemistry
The thematic issue "Computational Frontiers in Medicinal Chemistry" provides a robust platform for delving into state-of-the-art computational methodologies and technologies that significantly propel advancements in medicinal chemistry. This edition seeks to amalgamate top-tier reviews spotlighting the latest trends and breakthroughs in the fusion of computational approaches, including artificial intelligence (AI) ...read more
Natural Products and Dietary Supplements in Alleviation of Metabolic, Cardiovascular, and Neurological Disorders
Metabolic disorders like diabetes, obesity, inflammation, oxidative stress, cancer etc, cardiovascular disorders like angina, myocardial infarction, congestive heart failure etc as well as neurological disorders like Alzheimer?s, Parkinson?s, Epilepsy, Depression, etc are the global burden. They covered the major segment of the diseases and disorders from which the human community ...read more
Natural Products in Drug Discovery
Natural products have always been one of the important ways of drug discovery due to their novel skeleton and diverse functional group characteristics. According to statistics, between 1981 and 2019, the FDA approved a total of 1,394 small molecule drugs for marketing, of which 930 marketed drugs originated from the ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
Related Articles
-
Recent Advances in the Medicinal Chemistry of Sodium Channel Blockers and their Therapeutic Potential
Current Topics in Medicinal Chemistry A Concept of Homeostatic Inflammation Provided by Endogenous TLR4 Agonists that Function Before and After Danger Signal for Metastasis
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry Orchestrating HIV Neutralization by Secondary Immune Response- Mediated Induction of RF Antibodies
Current Immunology Reviews (Discontinued) 5-Lipoxygenase and Cyclooxygenase Inhibitory Dammarane Triterpenoid 1 from Borassus flabellifer Seed Coat Inhibits Tumor Necrosis Factor-α Secretion in LPSInduced THP-1 Human Monocytes and Induces Apoptosis in MIA PaCa-2 Pancreatic Cancer Cells
Anti-Cancer Agents in Medicinal Chemistry Chondroitin Sulfate and Sulfur Containing Chondroprotective Agents: Is there a Basis for their Pharmacological Action?
Current Rheumatology Reviews Therapeutic Strategies to Reverse Local Bone Loss in Erosive Arthritis
Current Rheumatology Reviews Prevalence and Risk Factors of Vitamin D Deficiency in Critically Ill Patients
Inflammation & Allergy - Drug Targets (Discontinued) Cognitive - Behavioral Therapy in Central Sensitivity Syndromes
Current Rheumatology Reviews Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Induced Dyspepsia
Current Pharmaceutical Design Recent Patents on Thiazole Derivatives Endowed with Antitumor Activity
Recent Patents on Anti-Cancer Drug Discovery Peripheral Mononuclear Cell Rejuvenation for Senescence Surveillance in Alzheimer Disease
Current Pharmaceutical Design Zinc and its Specific Transporters as Potential Targets in Airway Disease
Current Drug Targets Impact of IL-17 on Cells of the Monocyte Lineage in Health and Disease
Endocrine, Metabolic & Immune Disorders - Drug Targets The Crosstalk between Gut Inflammation and Gastrointestinal Disorders During Acute Pancreatitis
Current Pharmaceutical Design Angiogenesis-Related Proteins - Their Role in the Pathogenesis and Treatment of Inflammatory Bowel Disease
Current Protein & Peptide Science Designing, Optimisation & Characterization of Sustained Release Matrix Pellets Prepared by Extrusion Spheronization Containing Mixture of Proteolytic Enzymes
Current Drug Delivery Editorial (Thematic Issue: Metabolic Disorders, Drug Development, Drug Design and Biomarkers)
Current Pharmaceutical Design Pharmacological Activities and Therapeutic Potential of Kaempferitrin in Medicine for the Treatment of Human Disorders: A Review of Medicinal Importance and Health Benefits
Cardiovascular & Hematological Disorders-Drug Targets The Concept of Depression as a Dysfunction of the Immune System
Current Immunology Reviews (Discontinued) Schistosoma mansoni Antigens as Modulators of the Allergic Inflammatory Response in Asthma
Endocrine, Metabolic & Immune Disorders - Drug Targets