Importance of Understanding Enzyme’s Structure, Function and Regulation in Modern Drug Discovery

Importance of Understanding Enzyme’s Structure, Function and Regulation in Modern Drug Discovery

A Recent trend in medicine has been marked by the development of molecular science. Copeland explains that special interests have been directed in targeting particular macromolecules that are associated with a disease or has pathogenic bioactivity1. Enzymes are some of the prevalent biomolecules with continued exploitation in the development of drugs.  Enzymes have been associated with diseases processes, inhibition, and metabolism of drugs. Drug development can exploit such association. Moreover, enzymes have been exploited as drug targets2. Drug metabolism is also a critical issue in understanding pharmacokinetics such as therapeutic effects, side effects, and interindividual differences3.

This article seeks to evaluate the role of enzymes in the discovery of drugs. In achieving this, the article explores the role enzymes play in drug development. The article considers three aspects concerned with enzymes in their application in the discovery of new drugs. First, the article evaluates reasons for the use of enzymes as drug targets. Such application of enzymes reflects the role of structure in drug discovery and development1. As earlier mentioned, drug metabolism is of critical importance in drug discovery. Moreover, the paper performs an exploration of the role of drug metabolism in their developmentis also done. Such an exploration is pertinent in explaining how enzyme function and inhibition plays role in drug discovery.

Role of enzymes in drug discovery: The importance of structure, function and regulation

Enzymes are the primary molecules involved in catalysis1. The enzymes are composed of polypeptide chains that have a regular structural pattern. The structural scaffolding of an enzyme provides a spatial orientation that facilitates a specific catalysis reaction. Such specificity of the spatial configuration and prevalence of enzymes in catalytic reactions can be used as a drug target. For a drug to be effective, it is expected to exhibit some physicochemical properties. Such involve, be able to be absorbed, able to permeate cell membrane, be distributed and maintained in the body for some considerate amount of time.  These properties are formulated in consideration to the enzyme involved in the disease processes involved. Specificity of the drugs to a particular enzyme requires understating of the active site of an enzyme and hence their structural scaffolding. For instance, dihydrofolate reductase enzyme is involved in the biosynthesis of deoxythymidine. It is also the target for methotrexate drug.

Enzymes often undergo conformational changes in the course of the catalytic reaction. The change of substrate to products requires the change of enzymes from one structural form to another to facilitate the change1. The conformational changes of an enzyme are associated with the changes in the allosteric sites can be used as drug targets. Moreover, drugs can be used to alter the reaction mechanisms for therapeutic reasons by exploiting allosteric changes. Understanding these applications of enzymes requires an understanding of the structure and function of enzymes of interest.

Enzyme structure and active sites are pertinent to metabolism reaction of a drug that are exploited during preclinical tests of a new drugs3. The discovery phase of drug development involves identification of molecules with high efficacy towards a particular previously selected target. Such is of concern to determine the efficacy of the lead compound. This identification requires identifying the detecting of the active metabolites of the compound and an elucidation of the extent to which they interact with enzymes. Achieving these requirements of the discovery process requires an understanding of both enzyme structure and function. Enzyme structure is pertinent in explaining the degree of affinity of the metabolites to the enzyme. On the other hand, the function of the enzyme is essential in explaining the active metabolites of the lead compound.

The previous discussion introduces the aspect of efficacy and targetability of a drug. Targetability and efficacy of drugs is a critical area, and their improvement has been highly researched especially in the field of cancer treatment4. In achieving high targetability and efficacy of drugs, previous drug discovery processes have incorporated the use of prodrug technology. This technology allows the discovery if drug through the use of prodrugs that undergo transformation into their active forms through upon being acted on by enzymes. Enzyme actions involve such as cleaving, activation and conjugation of drugs to ligands.

The concepts of targetability of a drug are of importance only in the case when a suitable drug target has been identified5. Often, drug target identification has used the concept of Metabolic Control Analysis (MCA). MCA is favored in the identification of drug targets in that it does not involve characterization of all the components involved for a given drug. MCA helps to examine the various components of a  metabolic network contribution to provide a description of the signaling and metabolic system for various complexities. Cascante and colleagues explain that MCA is a description of the changes that occur in complex enzyme systems5. Therefore, understanding of the nature of enzymes is pertinent in selecting the target for a given drug. The following figure gives an example application of enzymes in drug target identification.

Fig 1: Use of chemical genetics in target identification and mechanism of action: This figure illustrates the process of target validation that is essential in indentifying a drug target. The process involves identifying the role of a disease or protein that is evaluated using biochemical assays to identify potential small molecules for drug targeting.


Source: Schenone et al. (2013)







Zawilska, Wojcieszak and Olejniczak explain that some biological systems in the body possess barriers4 overcomed through the exploitation of enzymes. For instance, drugs acting on the central nervous system have been difficult to develop previously due to the blood-brain barrier (BBB). Transport along the BBB is through the use of special carrier systems or by passive diffusion. The carrier molecules are enzyme systems and have been exploited to improve drug transport along the BBB. Moreover, drugs are formulated in such a way that prevents active efflux by enzymes from the brain. Abilities of a drug to exhibit these requirements require an understanding of the various enzymes involved, their structure and functioning.

Copeland explains that exclusion of drug metabolites from the biological systems requires an understanding of drug metabolism and pharmacokinetics1. Exclusion of drug molecules from the body involves various metabolic transformation of the drug into various metabolites. Often, enzymes achieve the catalysis of these transformations of the drugs. Therefore, appreciating of these processes requires an understanding of the nature of enzymes. The rate of the enzyme function, therefore, influences the bioavailability. Bioavailability of a drug can be predicted through an understanding of the interaction of a drug with enzymes that are responsible for the transformations.

Drugs may be formulated to act as enzyme inhibitors or may behave as such. In situations whereby a drug acts as an inhibitor causes accumulation of metabolites acted on by the enzyme involved1. Understanding of the effect of a drug on various enzymes is prudent in determining possible drug-drug interactions. Drug-drug interaction is often associated with side effects. For instance, co-administration of dofetilide and verapamil can cause an instance of drug-drug interaction. In this case, verapamil acts as an inhibitor of CYP3A4, a cytochrome P450 isozyme. CYP3A4 is responsible for the metabolism of dofetilide. CYP3A4 inhibition, therefore, causes accumulation of dofetilide that causes QT prolongation that can cause a fatal arrhythmia.


The discussion above indicates some of the areas where enzymes-ligand interactions are applied in the process of drug discovery. Enzymes have been shown to have active sites that can be used as binding sites for drugs or prodrugs. Active sites are specific and hence specificity of drugs is relatively high in the case of their use. Moreover, enzymes have been shown to undergo conformational changes in their structure. Such changes provide allosteric sites that act as potential and additional binding regions for drugs. Conformational changes also provide multiple ways through which a drug interacts with a target molecule. The discussion also draws the ability to evaluate the efficacy and targetability of a drug and in systematic pharmacology using the knowledge of metabolic reactions. Enzymes’ functioning, as characterized by MCA, has also been shown to be essential in the identification of drug targets.

This article has provided various features of enzymes that are of critical importance in drug discovery. These features can be summarized as active and allosteric sites and their interaction with molecules. Moreover, conformational changes are also pertinent in drug discovery.  The ability to evaluate the rate of reaction in MCA is also a pertinent feature. The ability of enzymes to transverse some membrane such as BBB is pertinent in the modern development of drugs for the central nervous system. These features can be understood through the consideration of the structure, function and regulation of enzymes. Therefore, an understanding of an enzyme’s structure, function and regulation are of critical importance in the modern discovery of drugs.



Cited References

  1. Copeland, R. A. Evaluation of enzyme inhibitors in drug discovery: a guide for medicinal chemists and pharmacologists. John Wiley & Sons. 2013.
  2. Williams, M. & Jeffrey B. M. Drug Discovery and Development. Clifton, N.J: Humana Press, 1987. Internet resource.
  3. Taavitsainen, Päivi, Paavo Honkakoski, Risto Juvonen, Olavi Pelkonen, and Hannu Raunio. Role of xenobiotic metabolism in drug discovery and development. : HD Unbehauen. Knowledge for Sustainable Development1.
  4. Zawilska, J. B., Wojcieszak, J., & Olejniczak, A. B. Prodrugs: a challenge for the drug development. Pharmacological Reports, 2013; 65(1), 1-14.
  5. Cascante, M., Boros, L. G., Comin-Anduix, B., de Atauri, P., Centelles, J. J., & Lee, P. W. N. Metabolic control analysis in drug discovery and disease.Nature biotechnology, 2002;20(3), 243-249.
  6. Schenone, M., Dančík, V., Wagner, B. K., & Clemons, P. A. Target identification and mechanism of action in chemical biology and drug discovery.Nature chemical biology, 2013; 9(4), 232-240.

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