Chemistry
Enzyme Inhibitors
Enzyme inhibitors are molecules that interfere with the activity of enzymes, which are biological catalysts. They can bind to the enzyme and prevent it from functioning properly, leading to a decrease in the rate of the enzyme-catalyzed reaction. Enzyme inhibitors are important in drug development and understanding biochemical pathways.
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9 Key excerpts on "Enzyme Inhibitors"
eBook - PDF- Rakesh R. Sharma(Author)
- 2012(Publication Date)
- IntechOpen(Publisher)
Section 1 Basic Concepts 1 Enzyme Inhibition: Mechanisms and Scope Rakesh Sharma 1,2,3 1 Center of Nanomagnetics Biotechnology, Florida State University, Tallahassee, FL 2 Innovations and Solutions Inc. USA, Tallahassee, FL 3 Amity University, NOIDA, UP 1,2 USA 3 India 1. Introduction Enzyme is a protein molecule acting as catalyst in enzyme reaction. Enzyme inhibition is a science of enzyme-substrate reaction influenced by the presence of any organic chemical or inorganic metal or biosynthetic compound due to their covalent or non-covalent interactions with enzyme active site. It is well known that all these inhibitors follow same rule to interplay in enzyme reaction. Present chapter introduces beginners with basic tenets of classic presumptions of enzyme inhibition, types of Enzyme Inhibitors, different models of enzyme inhibition with established examples cited in literature, and scientific basis of emerging immobilized enzyme technology in different applications. In the end, limitations of using classic presumptions and variants of enzyme inhibition are highlighted with new challenges to achieve best results. Present time, best approach is 'customize new technology with detailed analysis to make it highly efficient' in both drug discovery and enzyme biosensor industry. However, other applications are described in following chapters on pesticides, herbicides. 2. What are Enzyme Inhibitors? The Enzyme Inhibitors are low molecular weight chemical compounds. They can reduce or completely inhibit the enzyme catalytic activity either reversibly or permanently (irreversibly). Inhibitor can modify one amino acid, or several side chain(s) required in enzyme catalytic activity. To protect enzyme catalytic site from any change, ligand binds with critical side chain in enzyme. Safely, chemical modification can be done to test inhibitor for any drug value. In drug discovery, several drug analogues are chosen and/or designed to inhibit specific enzymes.
eBook - PDF- John R. Whitaker, Alphons G. J. Voragen, Dominic W.S. Wong, John R. Whitaker, Alphons G. J. Voragen, Dominic W.S. Wong(Authors)
- 2002(Publication Date)
- CRC Press(Publisher)
Nature of Inhibitors Enzyme Inhibitors are defined as any compound, except H+ ions (see pH effects), which decrease the activity when added to an enzyme reaction. Many enzyme inhi- bitors are known. They are used to kill insects or unwanted plants (herbicides) or animals (rotenone). They are used to prevent browning or preserve "fresh- ness" of fruits and vegetables. Many pharmaceutical compounds are designed to kill microorganisms by selectively inhibiting their enzyme systems. Mechanistically, there are two major groups of Enzyme Inhibitors. One group inhibits enzymes by reactions involving covalent bond formation (irrever- sible inhibitors); the other group inhibits enzymes by reversible noncovalent bond formation (reversible inhi- bitors). Both types are important as they decrease or eliminate enzyme activity. Enzyme-Catalyzed Reactions The rate and extent of inhibition of enzymes by irreversible inhibitors will depend on concentration of inhibitor, concentration of the enzyme, and the specific group modified on the enzyme, as well as pH and tem- perature. The rate of the inhibition will be relatively slow (minutes or hours) as a covalent bond is formed. The reaction cannot be reversed to regain enzyme activity. (31) B. Reversible Inhibitors The rate and extent of inhibition of enzymes by rever- sible inhibitors also depend on the factors listed above. However, the rate of inhibition is very rapid (msec) as a noncovalent complex is formed. Also, the inhibition can be reversed by removing the inhibitor (by dialysis or gel filtration). Our attention in this chapter is focused on the reversible Enzyme Inhibitors. Defined kinetically, a reversible inhibitor is one that reacts with an enzyme in a reversible manner as shown in Eq. (32), where Ki is an equilibrium (dissociation) con- stant. Ki = [E][l]fE ·I. (32) The reaction occurs within a few msec and the extent of inhibition is controlled by the concentration of E and I and Ki.
No longer available |Learn more- (Author)
- 2014(Publication Date)
- Library Press(Publisher)
A medicinal enzyme inhibitor is often judged by its specificity (its lack of binding to other proteins) and its potency (its dissociation constant, which indicates the concentration needed to inhibit the enzyme). A high specificity and potency ensure that a drug will have few side effects and thus low toxicity. ________________________ WORLD TECHNOLOGIES ________________________ Enzyme Inhibitors also occur naturally and are involved in the regulation of metabolism. For example, enzymes in a metabolic pathway can be inhibited by downstream products. This type of negative feedback slows flux through a pathway when the products begin to build up and is an important way to maintain homeostasis in a cell. Other cellular Enzyme Inhibitors are proteins that specifically bind to and inhibit an enzyme target. This can help control enzymes that may be damaging to a cell, such as proteases or nucleases; a well-characterised example is the ribonuclease inhibitor, which binds to ribonucleases in one of the tightest known protein–protein interactions. Natural Enzyme Inhibitors can also be poisons and are used as defences against predators or as ways of killing prey. Reversible inhibitors Types of reversible inhibitors Reversible inhibitors bind to enzymes with non-covalent interactions such as hydrogen bonds, hydrophobic interactions and ionic bonds. Multiple weak bonds between the inhibitor and the active site combine to produce strong and specific binding. In contrast to substrates and irreversible inhibitors, reversible inhibitors generally do not undergo chemical reactions when bound to the enzyme and can be easily removed by dilution or dialysis. Competitive inhibition: substrate (S) and inhibitor (I) compete for the active site There are four kinds of reversible Enzyme Inhibitors. They are classified according to the effect of varying the concentration of the enzyme's substrate on the inhibitor.
eBook - PDF- Murat Senturk(Author)
- 2017(Publication Date)
- IntechOpen(Publisher)
The linking of inhibitors can finish a substrate from the enzyme-active site and stays the enzyme in catalyzing in chemical reaction. Enzyme inhibition is both an irreversible and reversible process. The irreversible inhibi-tors react with enzyme and adjust it chemically by a covalent likening formation. Then, these inhibitors adjust important amino acid remnants wanted from an enzymatic reversible inhibi-tors which are non-covalently bonded; different types of inhibition are shaped depending on whether inhibitors link non-covalently, and dissimilar types of inhibition are shaped depending on whether these inhibitors bind to the enzyme and produced enzyme substrate complex or both [ 4 ]. Many natural products are Enzyme Inhibitors; the finding and development are dynamic areas of pharmacology and biochemistry. Medicinal Enzyme Inhibitors are frequently mediated by its specificity and its effectiveness that designated the absorption desirable to inhibit the enzyme. Great specificity and potency confirm that a medicinal drug will have few side effects and possess low toxicity. Natural Enzyme Inhibitors are involved in the guideline of much metabolic procedure. Actually, enzyme is a metabolic pathway which can be inhibited by many downstream yields. These types of bad response slow the manufacture line when product activates to shape up and a significant way to reserva-tion homeostasis in cell. An additional cellular enzyme inhibitor is protein which specially binds and inhibits an enzyme objective. These help regulator enzymes which may be harm-ful to cell alike proteases. The well-categorized example of this is the ribonuclease inhibitor that link ribonucleases in the tightest recognized protein contact. Many natural Enzyme Inhibitors may also be poisonous and are used as defenses besides predators as habits of killing several preys [ 4 ]. Enzyme Inhibitors and Activators 166
eBook - ePubPharmacology in Drug Discovery
Understanding Drug Response
- Terry P. Kenakin, Terry Kenakin(Authors)
- 2011(Publication Date)
- Academic Press(Publisher)
Chapter 6. Enzymes as Drug TargetsOutline
Introduction105New Terminology105Enzyme Kinetics107Enzymes as Drug Targets109Reversible Enzyme Inhibition112Irreversible Enzyme Inhibition117Intracellular Effects of Enzyme-Active Drugs120Summary123This chapter considers how enzymes can be therapeutic drug targets. The most common therapeutic approach to enzyme control is inhibition; there are four general classes of enzyme inhibition based on the relative affinity of the inhibitor for the enzyme and the enzyme–substrate complex. Competitive inhibition describes inhibitors that have exclusive affinity for the enzyme and compete for substrate binding. Mixed inhibitors bind to the enzyme and the enzyme–substrate complex with different affinity. Non-competitive inhibitors bind equally well to the enzyme and enzyme–substrate complex. Uncompetitive inhibitors bind only to the enzyme–substrate complex. There are special considerations for the blockade of enzymes in cells in that concentrations may differ (from the extracellular medium). In addition, Enzyme Inhibitors may have no effect until the enzyme is active metabolically under in vivo conditions. Finally, the topic of irreversible enzyme inhibition, enzyme activation and the special cases of drug action on intracellular enzymes is considered.Keywords catalysis, competitive inhibition, irreversible inhibition, mixed inhibition, non competitive inhibition, substrate inhibition, suicide inhibitor, tight-binding inhibitor, uncompetitive inhibition.By the end of this chapter students will understand how enzymes can be therapeutic drug targets. In addition, the four basic mechanisms of reversible enzyme inhibition, the topic of irreversible enzyme inhibition and enzyme activation will be discussed. Finally, the special cases of drug action on intracellular enzymes will be considered.
eBook - PDFEnzymes
A Practical Introduction to Structure, Mechanism, and Data Analysis
- Robert A. Copeland(Author)
- 2004(Publication Date)
- Wiley-Interscience(Publisher)
Such inhibitors hence are often referred to as enzyme inactivators. The first example of irreversible inhibition is the process known as affinity labeling or covalent modification of the enzyme. In this case, the inhibitory compound binds to the enzyme and covalently modifies a catalytically essential residue or residues on the enzyme. The covalent modification involves some chemical alteration of the inhibitory molecule, but the process is based on chemistry that occurs at the modification site in the absence of any enzyme- catalyzed reaction. Affinity labels are useful not only as inhibitors of enzyme activity; they also have become valuable research tools. Some of these com- pounds are very selective for specific amino acid residues and can thus be used to identify key residues involved in the catalytic cycle of the enzyme. See Section 10.5.3 and Lundblad (1991), and Copeland (1994). In the second form of irreversible inactivation we shall consider, mechanism- based inhibition, the inhibitory molecule binds to the enzyme active site and is recognized by the enzyme as a substrate analogue. The inhibitor is therefore chemically transformed through the catalytic mechanism of the enzyme to form an E — I complex that can no longer function catalytically. Many of these inhibitors inactivate the enzyme by forming an irreversible covalent E — I adduct. In other cases, the inhibitory molecule is subsequently released from the enzyme (a process referred to as noncovalent inactivation), but the enzyme has been permanently trapped in a form that can no longer support catalysis. Because they are chemically altered via the mechanism of enzymatic catalysis at the active site, mechanism-based inhibitors always act as competitive enzyme inactivators.
eBook - PDFEnzymes and Their Inhibitors
Drug Development
- H. John Smith, Claire Simons(Authors)
- 2004(Publication Date)
- CRC Press(Publisher)
186 Enzymes and Their Inhibition: Drug Development between functional groups of the inhibitor (e.g., –COCH 2 Cl, –COCHN 2 , –OCONHR, –SO 2 F) and enzyme (–SH, =N–, –NHR, –OH). A stable covalent bond is formed with irreversible inhibition of the enzyme. Active site-directed irreversible inhibitors are designed to exhibit speci fi city towards their target enzymes because they are structurally modeled on the speci fi c substrate of the enzyme concerned. These inhibitors are termed af fi nity-labeling agents when used to probe the nature of the functional groups present in the active site. Irreversible inhibitors progressively reduce enzyme activity with time, and the reaction follows pseudo-fi rst-order kinetics as described in Chapter 4. The biochem-ical environment of the enzyme (see Section 5.2.1) is unimportant so that any step in a biosynthetic pathway may be inhibited with decrease in overall metabolite production. However, because these compounds belong to a group that mainly consists of alkylating and acylating agents, they have not been developed as drugs as they would be expected to react with a range of tissue constituents containing amino or thiol groups besides the target enzyme, with potentially serious side effects. However, they have been used successfully as af fi nity labeling agents. 5.2.2.2.2 Mechanism-Based Enzyme Inactivators Many irreversible inhibitors of certain enzymes have previously been recognized, among which the range of electrophilic centers normally associated with active site-directed irreversible inhibitors, e.g., –COCH 2 Cl, –COCHN 2 , –OCONHR, –SO 2 F, were absent, and therefore the means by which they inhibited the enzyme was unclear. The action of these inhibitors has, in more recent years, become understand-able because they have been categorized as mechanism-based enzyme inactivators.
eBook - PDFEnzyme Technologies
Pluripotent Players in Discovering Therapeutic Agent
- Hsiu-Chiung Yang, Wu-Kuang Yeh, J. R. McCarthy(Authors)
- 2013(Publication Date)
- Wiley-Interscience(Publisher)
Edited by Hsiu-Chiung Yang, Wu-Kuang Yeh, and James R. McCarthy. © 2014 John Wiley & Sons, Inc. Published 2014 by John Wiley & Sons, Inc. 81 COVALENT ENZYME INHIBITION IN DRUG DISCOVERY AND DEVELOPMENT Shujaath Mehdi Immunoinflammation Therapeutic Strategy Unit, Sanofi Pharmaceuticals, Bridgewater, New Jersey 3 I. INTRODUCTION Enzyme inhibition is best viewed as a continuum (Fig. 1). At one extreme are inhib- itors for which the binding equilibrium is achieved rapidly (within seconds) and on the other are inhibitors whose complexes with the enzyme dissociate either not at all or too slowly to be easily measured. In addition to drugs that fall at either extreme, there are many that fall in-between, for which the dissociation half-life is of the order of several minutes to hours. (Such slowly reversible inhibitors are sometimes referred to as being “quasi-irreversible.”) For example, many ACE inhibitors, statins, and COX inhibitors exhibit slow-binding behavior (referring to the rate at which binding equilibrium is achieved, generally also having slow dissociation rates), to form non- covalent complexes that dissociate slowly; these are not discussed in the review. Irreversible inhibitors have been referred to as “covalent drugs”; however, covalent binding is neither necessary nor sufficient for irreversibility – there are examples of molecules that are noncovalently but irreversibly bound and also many examples of inhibitors that make covalent bonds that are more or less reversible. The key to reversibility is the type of covalent bond and its chemical stability, and its stability is a biological context (i.e., on the enzyme) – this is different for different types 82 COVALENT ENZYME INHIBITION IN DRUG DISCOVERY AND DEVELOPMENT of linkages (Fig. 2).
- H. J. Smith, Hywel Williams(Authors)
- 2016(Publication Date)
- Butterworth-Heinemann(Publisher)
By binding so much more strongly to the enzyme than does the substrate, it is more likely that this type of competitive reversible inhibitor would be more useful in therapy than the classical type of inhibitor which only resembles the structure of the substrate. This is because the action of the transition state analogue is less likely to be reversed by build-up of substrate (see p. 88). This point can readily be demonstrated by rearranging Equation 4.5 which gives the rate of the enzyme-catalysed reaction in the presence of a competitive inhibitor, to = ^max ( 4 3 5 ) [S] [S]*, This shows that, as the substrate concentration builds up, the second and third terms in the denominator decrease and v approaches K max . However, if KJKi is large (i.e. 10 3 ), for example when transition state analogues are used, the third term becomes less sensitive to an appreciable increase in the substrate concentration and the inhibition is, therefore, more persistent. 4.4.4 k cat Inhibitors as irreversible Enzyme Inhibitors Many irreversible inhibitors of certain enzymes have previously been recognized in which the range of electrophilic centres normally associated with active site-directed irreversible inhibitors were absent (see Table 4.2), so that the means by which they inhibited the enzyme was not understood. More recently the action of these inhibitors has become explicable since they have become characterized as k cat inhibitors. k cat Inhibitors bind to the enzyme through the K s parameter and are modified by the enzyme in such a way as to generate a reactive group which irreversibly inhibits the enzyme by forming a covalent bond with a functional DESIGN OF Enzyme Inhibitors (ANTIMETABOLITES) AS DRUGS 125 group present at the enzyme active site. These inhibitors are substrates of the enzyme as suggested by the term k cat which is the overall rate constant for the decomposition of the enzyme-substrate complex in an enzyme-catalysed reaction.
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