Human Copper-Containing Amine Oxidases in Drug Design and Development
Serhii Vakal1, Sirpa Jalkanen2, Käthe M Dahlström1
1Structural Bioinformatics Laboratory, Biochemistry, Faculty of Science and Engineering, Åbo Akademi University, Tykistökatu 6A, FI-20520 Turku, Finland.
Molecules (Basel, Switzerland)
|March 18, 2020
Summary
Designing inhibitors for vascular adhesion protein-1 (hVAP-1) requires careful consideration of diamine oxidase (hDAO) interactions to prevent adverse drug reactions. Structural bioinformatics and biology approaches can guide safer inhibitor design for inflammatory diseases and cancer.
Area of Science:
- Biochemistry
- Pharmacology
- Structural Biology
Background:
- Copper-containing amine oxidases, including diamine oxidase (hDAO) and vascular adhesion protein-1 (hVAP-1), are key physiological proteins.
- hVAP-1 inhibitors are developed for inflammatory diseases and cancer, but off-target binding to hDAO could cause adverse drug reactions.
- Understanding the structural and functional differences between hDAO and hVAP-1 is crucial for selective inhibitor design.
Purpose of the Study:
- To discuss considerations for designing hVAP-1 targeted inhibitors.
- To highlight the importance of structural bioinformatics and structural biology in inhibitor design.
- To emphasize the need to avoid off-target effects on hDAO and address species-specific binding properties.
Main Methods:
- Utilizing X-ray structures of human hDAO and hVAP-1 for computer-aided inhibitor design.
- Applying computational methods to predict and prevent off-target binding of hVAP-1 inhibitors to hDAO.
- Analyzing species-specific binding properties and amine oxidase repertoires in mammalian species.
Main Results:
- X-ray structures of hDAO and hVAP-1 provide a foundation for inhibitor design.
- Computational approaches can effectively mitigate the risk of hVAP-1 inhibitors binding to hDAO.
- Species-specific variations in copper-containing amine oxidases necessitate careful model organism selection for preclinical testing.
Conclusions:
- Inhibitor design targeting hVAP-1 must account for potential interactions with hDAO to ensure drug safety.
- Structural bioinformatics and structural biology are essential tools for developing selective and effective hVAP-1 inhibitors.
- Careful consideration of preclinical model systems is vital due to interspecies differences in amine oxidase families.
Related Concept Videos
01:17Drug Metabolism: Phase I Reactions
4.4K
A phase I reaction is a biochemical process that introduces a functionally reactive polar group to a substance. This transformation predominantly occurs in the liver, facilitated by the cytochrome P450 system of hemoproteins situated in the lipophilic endoplasmic reticulum of cells. The metabolite generated through this process can have varying polarities. If it is sufficiently polar, it can be easily excreted in the urine due to its water compatibility. However, if the metabolite is nonpolar,...
4.4K
01:15Phase I Reactions: Oxidation of Carbon-Heteroatom and Miscellaneous Systems
340
Oxidative reactions are pivotal in metabolizing numerous compounds, including pharmaceutical drugs. These reactions often occur in carbon-heteroatom systems, such as carbon-nitrogen, carbon-sulfur, and carbon-oxygen.
In carbon-nitrogen systems, aliphatic and aromatic amines can undergo oxidative reactions. Secondary and tertiary amines, like those found in tricyclic antidepressants, can undergo N-dealkylation, a process that involves the oxidation of the alkyl group. In addition, oxidative...
In carbon-nitrogen systems, aliphatic and aromatic amines can undergo oxidative reactions. Secondary and tertiary amines, like those found in tricyclic antidepressants, can undergo N-dealkylation, a process that involves the oxidation of the alkyl group. In addition, oxidative...
340
01:26Physical Properties of Amines
4.0K
Amines with low molecular weight are usually gaseous at room temperature, while those with high molecular weight are liquid or solids in nature. Usually, low molecular weight amines have a rotten fish-like smell. Diamines typically have a pungent smell. For instance, cadaverine and putrescine, depicted in Figure 1, are two molecules responsible for decaying tissue.
4.0K
01:29Preparation of Amines: Reduction of Oximes and Nitro Compounds
4.5K
Oximes can be reduced to primary amines using catalytic hydrogenation, hydride reduction, or sodium metal reduction. The reduction of aliphatic and aromatic nitro compounds to primary amines takes place by either catalytic hydrogenation or by using active metals like Fe, Zn, and Sn in the presence of an acid.
Though catalytic hydrogenation can reduce nitrobenzenes, the reduction is nonselective in the presence of other functional groups. For instance, if nitrobenzene contains an aldehyde group,...
Though catalytic hydrogenation can reduce nitrobenzenes, the reduction is nonselective in the presence of other functional groups. For instance, if nitrobenzene contains an aldehyde group,...
4.5K
01:14Drug Metabolism: Phase II Reactions
4.8K
Phase II reactions are essential for the detoxification and elimination of drugs from the body. These reactions involve the conjugation of parent drugs or their phase I metabolites with endogenous molecules, resulting in more hydrophilic drug conjugates. The primary conjugation reactions in this phase are sulfation and glucuronidation. Both sulfation and glucuronidation typically produce biologically inactive metabolites. However, in some cases involving prodrugs, active metabolites may be...
4.8K
01:26Drug Discovery: Overview
10.8K
Drug discovery is a multifaceted process involving extensive screening, testing, and optimization of lead compounds to identify potential new drugs for therapeutic use. It combines several approaches, including screening large numbers of natural products, chemical modification of known active molecules, identification of new drug targets, and rational design based on biological mechanisms and drug-receptor structure. These approaches are carried out in both academic research laboratories and...
10.8K