Abstract
Making reliable predictions of drug metabolites requires detailed knowledge of the chemical reactivity of drug metabolizing enzymes. Cytochrome P450 enzymes (P450s) play an important role in drug metabolism. Numerous adverse drug reactions have been identified that occur as a result of interactions with P450s. These enzymes display complex reactivity and the active oxidizing species is highly reactive and difficult to isolate, making P450s ideal candidates for computational study. Hybrid quantum mechanics/molecular mechanics calculations (QM/MM) have provided valuable insight into the reactivity of P450s, and will assist in the development of simpler predictive models. QM/MM methods have been used to model the metabolism of several drug molecules in human P450s, and have successfully rationalized experimentally observed selectivity. QM/MM calculations have been used to investigate the reactivity of other drug metabolizing enzymes, such as soluble epoxide hydrolase and glutathione transferases. Here, we review the application of QM/MM methods to modelling reactions catalyzed by drug metabolizing enzymes.
Keywords: Cytochrome P450, drug metabolism, enzymes, epoxide hydrolase, modelling, quantum mechanics/molecular mechanics, selectivity.
Current Topics in Medicinal Chemistry
Title:QM/MM Modelling of Drug-Metabolizing Enzymes
Volume: 14 Issue: 11
Author(s): Richard Lonsdale and Adrian J. Mulholland
Affiliation:
Keywords: Cytochrome P450, drug metabolism, enzymes, epoxide hydrolase, modelling, quantum mechanics/molecular mechanics, selectivity.
Abstract: Making reliable predictions of drug metabolites requires detailed knowledge of the chemical reactivity of drug metabolizing enzymes. Cytochrome P450 enzymes (P450s) play an important role in drug metabolism. Numerous adverse drug reactions have been identified that occur as a result of interactions with P450s. These enzymes display complex reactivity and the active oxidizing species is highly reactive and difficult to isolate, making P450s ideal candidates for computational study. Hybrid quantum mechanics/molecular mechanics calculations (QM/MM) have provided valuable insight into the reactivity of P450s, and will assist in the development of simpler predictive models. QM/MM methods have been used to model the metabolism of several drug molecules in human P450s, and have successfully rationalized experimentally observed selectivity. QM/MM calculations have been used to investigate the reactivity of other drug metabolizing enzymes, such as soluble epoxide hydrolase and glutathione transferases. Here, we review the application of QM/MM methods to modelling reactions catalyzed by drug metabolizing enzymes.
Export Options
About this article
Cite this article as:
Lonsdale Richard and Mulholland J. Adrian, QM/MM Modelling of Drug-Metabolizing Enzymes, Current Topics in Medicinal Chemistry 2014; 14 (11) . https://dx.doi.org/10.2174/1568026614666140506114859
DOI https://dx.doi.org/10.2174/1568026614666140506114859 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
Call for Papers in Thematic Issues
Chemistry Based on Natural Products for Therapeutic Purposes
The development of new pharmaceuticals for a wide range of medical conditions has long relied on the identification of promising natural products (NPs). There are over sixty percent of cancer, infectious illness, and CNS disease medications that include an NP pharmacophore, according to the Food and Drug Administration. Since NP ...read more
Current Trends in Drug Discovery Based on Artificial Intelligence and Computer-Aided Drug Design
Drug development discovery has faced several challenges over the years. In fact, the evolution of classical approaches to modern methods using computational methods, or Computer-Aided Drug Design (CADD), has shown promising and essential results in any drug discovery campaign. Among these methods, molecular docking is one of the most notable ...read more
Drug Discovery in the Age of Artificial Intelligence
In the age of artificial intelligence (AI), we have witnessed a significant boom in AI techniques for drug discovery. AI techniques are increasingly integrated and accelerating the drug discovery process. These developments have not only attracted the attention of academia and industry but also raised important questions regarding the selection ...read more
From Biodiversity to Chemical Diversity: Focus of Flavonoids
Flavonoids are the largest group of polyphenols, plant secondary metabolites arising from the essential aromatic amino acid phenylalanine (or more rarely from tyrosine) via the phenylpropanoid pathway. The flavan nucleus is the basic 15-carbon skeleton of flavonoids (C6-C3-C6), which consists of two phenyl rings (A and B) and a heterocyclic ...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
- Announcements
Related Articles
-
Is Hypertension an Inflammatory Process?
Current Pharmaceutical Design Inflammation, Oxidation, Caloric Expenditure and Cognitive Impairment in Brazilian Elderly Assisted at Primary Care
Current Alzheimer Research Consumption of Polyphenol Plants May Slow Aging and Associated Diseases
Current Pharmaceutical Design Mechanistic View of Renal Protective Action of Calcium Channel Blockade
Current Hypertension Reviews Thyroid Disorders in Chronic Heart Failure: From Prognostic Set-up to Therapeutic Management
Endocrine, Metabolic & Immune Disorders - Drug Targets Cyclooxygenases Regulation by Estradiol on Endothelium
Current Pharmaceutical Design Exercise and Cardiovascular Disease
Cardiovascular & Hematological Disorders-Drug Targets Synthesis and Biological Activity of 3-(substitutedphenyl)- 6-(4-methoxyphenyl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine
Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Discontinued) Link between Metabolic Syndrome and Insulin Resistance
Current Vascular Pharmacology The Oxygen Therapy
Current Medicinal Chemistry Mobile Phone Based Health Care Technology
Recent Patents on Biomedical Engineering (Discontinued) Determination of Propranolol and Naproxen in Urine by using Excitation-Emission Matrix Phosphorescence Coupled with Multivariate Calibration Algorithms
Current Pharmaceutical Analysis Urocortins: Take Them to Heart
Current Medicinal Chemistry - Cardiovascular & Hematological Agents Nitric Oxide as a Marker for Levo-Thyroxine Therapy in Subclinical Hypothyroid Patients
Current Vascular Pharmacology Class- and Molecule-specific Differential Effects of Angiotensin II Type 1 Receptor Blockers
Current Pharmaceutical Design Myxedema Heart Disease: A Rare Disease Entity: Case Report and Brief Review of the Literature
Current Hypertension Reviews “Metabolically Healthy” Obesity: Fact or Threat?
Current Diabetes Reviews Recent Developments in the Field of Quinazoline Chemistry
Current Organic Chemistry Chemistry and Effects of Brainstem Acting Drugs
Central Nervous System Agents in Medicinal Chemistry Omega-3 Fatty Acids for Nutrition and Medicine: Considering Microalgae Oil as a Vegetarian Source of EPA and DHA
Current Diabetes Reviews