Drugs and Drug Targets: An Overview PDF

Drugs and drug targets: 1 an overview 1.1 What is a drug? such example. It is an excellent analgesic, yet there are serious side effects, such as tolerance, respir...

Drugs and drug targets: 1 an overview 1.1 What is a drug? such example. It is an excellent analgesic, yet there are serious side effects, such as tolerance, respiratory The medicinal chemist attempts to design and synthe- depression, and addiction. It can even kill if taken in size a pharmaceutical agent that has a desired biological excess. effect on the human body or some other living system. Barbiturates are also known to be dangerous. At Pearl Such a compound could also be called a ‘drug’, but this is Harbor, American casualties were given barbiturates as a word that many scientists dislike because society views general anaesthetics before surgery. However, because of the term with suspicion. With media headlines such as a poor understanding about how barbiturates are stored ‘Drugs Menace’ or ‘Drug Addiction Sweeps City Streets’, in the body, many patients received sudden and fatal this is hardly surprising. However, it suggests that a dis- overdoses. In fact, it is thought that more casualties died tinction can be drawn between drugs that are used in at the hands of the anaesthetists at Pearl Harbor than medicine and drugs that are abused. Is this really true? died of their wounds. Can we draw a neat line between ‘good drugs’ like peni- To conclude, the ‘good’ drugs are not as perfect as one cillin and ‘bad drugs’ like heroin? If so, how do we define might think. what is meant by a good or a bad drug in the first place? What about the ‘bad’ drugs then? Is there anything Where would we place a so-called social drug like canna- good that can be said about them? Surely there is nothing bis in this divide? What about nicotine or alcohol? we can say in defence of the highly addictive drug known The answers we get depend on who we ask. As far as as heroin? the law is concerned, the dividing line is defined in black Well, let us look at the facts about heroin. It is one of and white. As far as the party-going teenager is con- the best painkillers we know. In fact, it was named her- cerned, the law is an ass. As far as we are concerned, the oin at the end of the nineteenth century because it was questions are irrelevant. Trying to divide drugs into two thought to be the ‘heroic’ drug that would banish pain categories—safe or unsafe, good or bad—is futile and for good. Heroin went on the market in 1898, but five could even be dangerous. years later the true nature of its addictive properties First, let us consider the so-called ‘good’ drugs used in became evident and the drug was speedily withdrawn medicines. How ‘good’ are they? If a drug is to be truly from general distribution. However, heroin is still used ‘good’ it would have to do what it is meant to do, have no in medicine today—under strict control, of course. The toxic or unwanted side effects, and be easy to take. drug is called diamorphine and it is the drug of choice How many drugs fit these criteria? for treating patients dying of cancer. Not only does The short answer is ‘none’. There is no pharmaceutical diamorphine reduce pain to acceptable levels, it also pro- compound on the market today that can completely satisfy duces a euphoric effect that helps to counter the depression all these conditions. Admittedly, some come quite close to faced by patients close to death. Can we really condemn the ideal. Penicillin, for example, has been one of the saf- a drug which does that as being all ‘bad’? est and most effective antibacterial agents ever discovered. By now it should be evident that the division between Yet, it too has drawbacks. It cannot kill all known bacteria good drugs and bad drugs is a woolly one and is not and, as the years have gone by, more and more bacterial really relevant to our discussion of medicinal chemistry. strains have become resistant. Moreover, some individuals All drugs have their good and bad points. Some have can experience severe allergic reactions to the compound. more good points than bad and vice versa, but, like peo- Penicillin is a relatively safe drug, but there are some ple, they all have their own individual characteristics. So drugs that are distinctly dangerous. Morphine is one how are we to define a drug in general? 2 Chapter 1 Drugs and drug targets: an overview One definition could be to classify drugs as ‘compounds There is a term used in medicinal chemistry known as which interact with a biological system to produce a the therapeutic index, which indicates how safe a par- biological response’. This definition covers all the drugs ticular drug is. The therapeutic index is a measure of the we have discussed so far, but it goes further. There are drug’s beneficial effects at a low dose versus its harmful chemicals that we take every day and which have a bio- effects at a high dose. To be more precise, the therapeutic logical effect on us. What are these everyday drugs? index compares the dose level required to produce toxic One is contained in all the cups of tea, coffee, and effects in 50% of patients with the dose level required cocoa that we consume. All of these beverages contain to produce the maximum therapeutic effects in 50% of the stimulant caffeine. Whenever you take a cup of cof- patients. A high therapeutic index means that there is a fee, you are a drug user. We could go further. Whenever large safety margin between beneficial and toxic doses. you crave a cup of coffee, you are a drug addict. Even The values for cannabis and alcohol are 1000 and 10, children are not immune. They get their caffeine ‘shot’ respectively, which might imply that cannabis is safer and from Coke or Pepsi. Whether you like it or not, caffeine more predictable than alcohol. Indeed, a cannabis prepa- is a drug. When you take it, you experience a change of ration (nabiximols) has now been approved to relieve the mood or feeling. symptoms of multiple sclerosis. However, this does not So too, if you are a worshipper of the ‘nicotine stick’. suddenly make cannabis safe. For example, the favour- The biological effect is different. In this case you crave able therapeutic index of cannabis does not indicate its sedation or a calming influence, and it is the nicotine in potential toxicity if it is taken over a long period of time the cigarette smoke which induces that effect. (chronic use). For example, the various side effects of There can be little doubt that alcohol is a drug and, as cannabis include panic attacks, paranoid delusions, and such, causes society more problems than all other drugs hallucinations. Clearly, the safety of drugs is a complex put together. One only has to study road accident statistics matter and it is not helped by media sensationalism. to appreciate that fact. If alcohol was discovered today, it If useful drugs can be poisons at high doses or over would probably be restricted in exactly the same way as long periods of use, does the opposite hold true? Can a cocaine. Considered in a purely scientific way, alcohol poison be a medicine at low doses? In certain cases, this is a most unsatisfactory drug. As many will testify, it is is found to be so. notoriously difficult to judge the correct dose required to Arsenic is well known as a poison, but arsenic-derived gain the beneficial effect of ‘happiness’ without drifting compounds are used as antiprotozoal and anticancer into the higher dose levels that produce unwanted side agents. Curare is a deadly poison which was used by effects, such as staggering down the street. Alcohol is also the native people of South America to tip their arrows unpredictable in its biological effects. Either happiness or such that a minor arrow wound would be fatal, yet com- depression may result, depending on the user’s state of pounds based on the tubocurarine structure (the active mind. On a more serious note, addiction and tolerance principle of curare) are used in surgical operations to in certain individuals have ruined the lives of addicts and relax muscles. Under proper control and in the correct relatives alike. dosage, a lethal poison may well have an important medi- Our definition of a drug can also be used to include cal role. Alternatively, lethal poisons can be the starting other compounds which may not be obvious as drugs, for point for the development of useful drugs. For example, example poisons and toxins. They too interact with a bio- ACE inhibitors are important cardiovascular drugs that logical system and produce a biological response—a bit were developed, in part, from the structure of a snake extreme, perhaps, but a response all the same. The idea of venom. poisons acting as drugs may not appear so strange if we As our definition covers any chemical that interacts consider penicillin. We have no problem in thinking of with any biological system, we could include all pesti- penicillin as a drug, but if we were to look closely at how cides and herbicides as drugs. They interact with bacte- penicillin works, then it is really a poison. It interacts ria, fungi, and insects, kill them, and thus protect plants. with bacteria (the biological system) and kills them (the Even food can act like a drug. Junk foods and fizzy drinks biological response). Fortunately for us, penicillin has no have been blamed for causing hyperactivity in children. It such effect on human cells. is believed that junk foods have high concentrations of Even those drugs which do not act as poisons have the certain amino acids which can be converted in the body to potential to become poisons—usually if they are taken neurotransmitters. These are chemicals that pass messages in excess. We have already seen this with morphine. At between nerves. If an excess of these chemical messengers low doses it is a painkiller; at high doses, it is a poison should accumulate, then too many messages are trans- which kills by the suppression of breathing. Therefore, it mitted in the brain, leading to the disruptive behaviour is important that we treat all medicines as potential poi- observed in susceptible individuals. Allergies due to food sons and treat them with respect. additives and preservatives are also well recorded.  Drug targets 3 Some foods even contain toxic chemicals. Broccoli, a complicated and large structure as a human being? The cabbage, and cauliflower all contain high levels of a answer lies in the way that the human body operates. If chemical that can cause reproductive abnormalities in we could see inside our bodies to the molecular level, we rats. Peanuts and maize sometimes contain fungal toxins, would see a magnificent array of chemical reactions tak- and it is thought that fungal toxins in food were respon- ing place, keeping the body healthy and functioning. sible for the biblical plagues. Basil contains over 50 com- Drugs may be mere chemicals, but they are entering pounds that are potentially carcinogenic, and other herbs a world of chemical reactions with which they interact. contain some of the most potent carcinogens known. Therefore, there should be nothing odd in the fact that Carcinogenic compounds have also been identified in they can have an effect. The surprising thing might be radishes, brown mustard, apricots, cherries, and plums. that they can have such specific effects. This is more a Such unpalatable facts might put you off your dinner, but result of where they act in the body—the drug targets. take comfort—these chemicals are present in such small quantities that the risk is insignificant. Therein lies a great 1.2.1 Cell structure truth, which was recognized as long ago as the fifteenth century when it was stated that ‘Everything is a poison, As life is made up of cells, then quite clearly drugs must nothing is a poison. It is the dose that makes the poison’. act on cells. The structure of a typical mammalian cell is Almost anything taken in excess will be toxic. You can shown in Fig. 1.1. All cells in the human body contain a make yourself seriously ill by taking 100 aspirin tablets or boundary wall called the cell membrane which encloses a bottle of whisky or 9 kg of spinach. The choice is yours! the contents of the cell—the cytoplasm. The cell mem- To conclude, drugs can be viewed as actual or poten- brane seen under the electron microscope consists of tial poisons. An important principle is that of selective two identifiable layers, each of which is made up of an toxicity. Many drugs are effective because they are toxic ordered row of phosphoglyceride molecules, such as to ‘problem cells’, but not normal cells. For example, anti- phosphatidylcholine (lecithin) (Fig. 1.2). The outer layer bacterial, antifungal, and antiprotozoal drugs are use- of the membrane is made up of phosphatidylcholine, ful in medicine when they show a selective toxicity to whereas the inner layer is made up of phosphatidyletha- microbial cells, rather than mammalian cells. Clinically nolamine, phosphatidylserine, and phosphatidylinosi- effective anticancer agents show a selective toxicity for tol. Each phosphoglyceride molecule consists of a small cancer cells over normal cells. Similarly, effective antivi- polar head-group and two long, hydrophobic (water- ral agents are toxic to viruses rather than normal cells. hating) chains. Having discussed what drugs are, we shall now con- In the cell membrane, the two layers of phospholipids are sider why, where, and how they act. arranged such that the hydrophobic tails point towards each other and form a fatty, hydrophobic centre, while KEY POINTS the ionic head-groups are placed at the inner and outer surfaces of the cell membrane (Fig. 1.3). This is a stable Drugs are compounds that interact with a biological system structure because the ionic, hydrophilic head-groups to produce a biological response. No drug is totally safe. Drugs vary in the side effects they might have. The dose level of a compound determines whether it will act as a medicine or as a poison. Cytoplasm The therapeutic index is a measure of a drug’s beneficial effect at a low dose versus its harmful effects at higher dose. A high therapeutic index indicates a large safety margin between beneficial and toxic doses. Nucleus The principle of selective toxicity means that useful drugs show toxicity against foreign or abnormal cells but not against Nuclear normal host cells. membrane Cell membrane 1.2 Drug targets FIGURE 1.1 A typical mammalian cell. Taken from Why should chemicals, some of which have remarkably Mann, J. (1992) Murder, Magic, and Medicine. Oxford simple structures, have such an important effect on such University Press, with permission. 4 Chapter 1 Drugs and drug targets: an overview These carbohydrate segments are important in cell–cell NMe3 Polar (CH2)2 recognition (section 10.7). head O Within the cytoplasm there are several structures, one group O P O of which is the nucleus. This acts as the ‘control centre’ Polar O for the cell. The nucleus contains the genetic code—the head CH2 CH CH2 DNA—which acts as the blueprint for the construction group O O of all the cell’s proteins. There are many other structures O O within a cell, such as the mitochondria, the Golgi appa- ratus, and the endoplasmic reticulum, but it is not the purpose of this book to look at the structure and func- Hydrophobic tion of these organelles. Suffice it to say that different Hydrophobic tails tails drugs act on molecular targets at different locations in the cell. 1.2.2 Drug targets at the molecular level FIGURE 1.2 Phosphoglyceride structure. We shall now move to the molecular level, because it is here that we can truly appreciate how drugs work. The main molecular targets for drugs are proteins (mainly interact with the aqueous media inside and outside the enzymes, receptors, and transport proteins) and nucleic cell, whereas the hydrophobic tails maximize hydro- acids (DNA and RNA). These are large molecules phobic interactions with each other and are kept away (macromolecules) that have molecular weights meas- from the aqueous environments. The overall result of this ured in the order of several thousand atomic mass units. structure is to construct a fatty barrier between the cell’s They are much bigger than the typical drug, which has a interior and its surroundings. molecular weight in the order of a few hundred atomic The membrane is not just made up of phospholipids, mass units. however. There are a large variety of proteins situated in The interaction of a drug with a macromolecular tar- the cell membrane (Fig. 1.3). Some proteins lie attached get involves a process known as binding. There is usu- to the inner or the outer surface of the membrane. Others ally a specific area of the macromolecule where this takes are embedded in the membrane with part of their struc- place, known as the binding site (Fig. 1.4). Typically, this ture exposed to one surface or both. The extent to which takes the form of a hollow or canyon on the surface of these proteins are embedded within the cell membrane the macromolecule allowing the drug to sink into the structure depends on the types of amino acid present. body of the larger molecule. Some drugs react with the Portions of protein that are embedded in the cell mem- binding site and become permanently attached via a brane have a large number of hydrophobic amino acids, covalent bond that has a bond strength of 200–400 kJ whereas those portions that stick out from the surface mol−1. However, most drugs interact through weaker have a large number of hydrophilic amino acids. Many forms of interaction known as intermolecular bonds. surface proteins also have short chains of carbohydrates These include electrostatic or ionic bonds, hydrogen attached to them and are thus classed as glycoproteins. bonds, van der Waals interactions, dipole–dipole inter- actions, and hydrophobic interactions. (It is also possible for these interactions to take place within a molecule, in which case they are called intramolecular bonds; see for example protein structure, sections 2.2 and 2.3.) None of these bonds is as strong as the covalent bonds that make up the skeleton of a molecule, and so they can be formed Glycoprotein and then broken again. This means that an equilibrium takes place between the drug being bound and unbound to its target. The binding forces are strong enough to Lipid bilayer hold the drug for a certain period of time to let it have an effect on the target, but weak enough to allow the drug to depart once it has done its job. The length of time the FIGURE 1.3 Cell membrane. Taken from Mann, J. (1992) drug remains at its target will then depend on the num- Murder, Magic, and Medicine. Oxford University Press, ber of intermolecular bonds involved in holding it there. with permission. Drugs that have a large number of interactions are likely  Intermolecular bonding forces 5 Binding regions Drug Binding groups Intermolecular bonds Binding site Drug Binding site Drug Induced fit Macromolecular target Macromolecular target Unbound drug Bound drug FIGURE 1.4 The equilibrium of a drug being bound and unbound to its target. to remain bound longer than those that have only a few. and types of these interactions depend on the structure The relative strength of the different intermolecular bind- of the drug and the functional groups that are present ing forces is also an important factor. Functional groups (section 13.1 and Appendix 7). Thus, each drug may use present in the drug can be important in forming inter- one or more of the following interactions, but not neces- molecular bonds with the target binding site. If they do sarily all of them. so, they are called binding groups. However, the carbon skeleton of the drug also plays an important role in bind- 1.3.1 Electrostatic or ionic bonds ing the drug to its target through van der Waals interac- tions. As far as the target binding site is concerned, it too An ionic or electrostatic bond is the strongest of the contains functional groups and carbon skeletons which intermolecular bonds (20–40 kJ mol−1) and takes place can form intermolecular bonds with ‘visiting’ drugs. between groups that have opposite charges, such as The specific regions where this takes place are known as a carboxylate ion and an aminium ion (Fig. 1.5). The binding regions. The study of how drugs interact with strength of the interaction is inversely proportional to their targets through binding interactions and produce the distance between the two charged atoms and it is a pharmacological effect is known as pharmacodynamics. also dependent on the nature of the environment, being Let us now consider the types of intermolecular bond stronger in hydrophobic environments than in polar envi- that are possible. ronments. Usually, the binding sites of macromolecules are more hydrophobic in nature than the surface and so this enhances the effect of an ionic interaction. The drop- 1.3 Intermolecular bonding forces off in ionic bonding strength with separation is less than in other intermolecular interactions, so if an ionic interac- There are several types of intermolecular bonding inter- tion is possible, it is likely to be the most important initial actions, which differ in their bond strengths. The number interaction as the drug enters the binding site. O Drug Drug NH3 O O H3N Target Target O FIGURE 1.5 Electrostatic (ionic) interactions between a drug and the binding site. 6 Chapter 1 Drugs and drug targets: an overview δ– δ+ δ– δ– δ+ δ– Drug Y H X X H Y Target Target Drug HBD HBA HBA HBD FIGURE 1.6 Hydrogen bonding shown by a dashed line between a drug and a binding site (X, Y = oxygen or nitrogen; HBD = hydrogen bond donor, HBA = hydrogen bond acceptor). weak form of sigma (σ) bonding and has an important 1.3.2 Hydrogen bonds directional consequence that is not evident in electro- A hydrogen bond can vary substantially in strength and static bonds. The optimum orientation is where the normally takes place between an electron-rich hetero- X–H bond points directly to the lone pair on Y such that atom and an electron-deficient hydrogen (Fig. 1.6). The the angle formed between X, H, and Y is 180°. This is electron-rich heteroatom has to have a lone pair of elec- observed in very strong hydrogen bonds. However, the trons and is usually oxygen or nitrogen. angle can vary between 130° and 180° for moderately The electron-deficient hydrogen is usually linked by a strong hydrogen bonds, and can be as low as 90° for weak covalent bond to an electronegative atom, such as oxy- hydrogen bonds. The lone pair orbital of Y also has a gen or nitrogen. As the electronegative atom (X) has a directional property depending on its hybridization. For greater attraction for electrons, the electron distribu- example, the nitrogen of a pyridine ring is sp2 hybridized tion in the covalent bond (X–H) is weighted towards the and so the lone pair points directly away from the ring more electronegative atom and so the hydrogen gains its and in the same plane (Fig. 1.8). The best location for a slight positive charge. The functional group containing hydrogen bond donor would be the region of space indi- this feature is known as a hydrogen bond donor (HBD) cated in the figure. because it provides the hydrogen for the hydrogen bond. The strength of a hydrogen bond can vary widely, but The functional group that provides the electron-rich atom most hydrogen bonds in drug–target interactions are to receive the hydrogen bond is known as the hydrogen moderate in strength, varying from 16 to 60 kJ mol−1— bond acceptor (HBA). Some functional groups can approximately 10 times less than a covalent bond. The act both as hydrogen bond donors and hydrogen bond bond distance reflects this; hydrogen bonds are typi- acceptors (e.g. OH, NH2). When such a group is present cally 1.5–2.2 Å compared with 1.0–1.5 Å for a covalent in a binding site, it is possible that it might bind to one bond. The strength of a hydrogen bond depends on how ligand as a hydrogen bond donor and to another as a strong the hydrogen bond acceptor and the hydrogen hydrogen bond acceptor. This characteristic is given the bond donor are. A good hydrogen bond acceptor has term hydrogen bond flip-flop. to be electronegative and have a lone pair of electrons. Hydrogen bonds have been viewed as a weak form Nitrogen and oxygen are the most common atoms of electrostatic interaction because the heteroatom is involved as hydrogen bond acceptors in biological sys- slightly negative and the hydrogen is slightly positive. tems. Nitrogen has one lone pair of electrons and can act However, there is more to hydrogen bonding than an as an acceptor for one hydrogen bond; oxygen has two attraction between partial charges. Unlike other inter- lone pairs of electrons and can act as an acceptor for two molecular interactions, an interaction of orbitals takes hydrogen bonds (Fig. 1.9). place between the two molecules (Fig. 1.7). The orbital Several drugs and macromolecular targets contain a containing the lone pair of electrons on heteroatom (Y) sulphur atom, which is also electronegative. However, interacts with the atomic orbitals normally involved in sulphur is a weak hydrogen bond acceptor because its lone the covalent bond between X and H. This results in a pairs are in third-shell orbitals that are larger and more X H Y X H Y Hybridized 1s Hybridized orbital orbital orbital FIGURE 1.7 Orbital overlap in a hydrogen bond.  Intermolecular bonding forces 7 sp2 that fluorine is so electronegative that it clings on tightly to its lone pairs of electrons, making them incapable of R N hydrogen bond interactions. This is in contrast to fluo- HBA N H X ride ions which are very strong hydrogen bond acceptors. Any feature that affects the electron density of the H hydrogen bond acceptor is likely to affect its ability to HBD X act as a hydrogen bond acceptor; the greater the electron R density of the heteroatom, the greater its strength as a FIGURE 1.8 Directional influence of hybridization on hydrogen bond acceptor. For example, the oxygen of a hydrogen bonding. negatively charged carboxylate ion is a stronger hydrogen bond acceptor than the oxygen of the uncharged carbox- ylic acid (Fig. 1.10). Phosphate ions can also act as good hydrogen bond acceptors. Most hydrogen bond acceptors XR HBD present in drugs and binding sites are neutral functional HBD RX XR HBD H H H groups, such as ethers, alcohols, phenols, amides, amines, and ketones. These groups will form moderately strong O N HBA hydrogen bonds. R R R R It has been proposed that the pi (π) systems present in R HBA alkynes and aromatic rings are regions of high electron FIGURE 1.9 Oxygen and nitrogen acting as hydrogen bond density and can act as hydrogen bond acceptors. However, acceptors (HBD = hydrogen bond donor, HBA = hydrogen the electron density in these systems is diffuse and so the bond acceptor). hydrogen bonding interaction is much weaker than those involving oxygen or nitrogen. As a result, aromatic rings and alkynes are only likely to be significant hydrogen diffuse. This means that the orbitals concerned interact bond acceptors if they interact with a strong hydrogen less efficiently with the small 1s orbitals of hydrogen atoms. bond donor, such as an alkylammonium ion (NHR3+). Fluorine, which is present in several drugs, is more More subtle effects can influence whether an atom is electronegative than either oxygen or nitrogen. It also has a good hydrogen bond acceptor or not. For example, the three lone pairs of electrons, which might suggest that it nitrogen atom of an aliphatic tertiary amine is a better would make a good hydrogen bond acceptor. In fact, it hydrogen bond acceptor than the nitrogen of an amide is a weak hydrogen bond acceptor. It has been suggested or an aniline (Fig. 1.11). In the latter cases, the lone pair O O O R O O R C R P O R C R O R O R N O O OH H R R R R R XR Strong HBAs Moderate HBAs R R S R F R Cl R C C R Weak HBAs FIGURE 1.10 Relative strengths of hydrogen bond acceptors (HBAs). O O R R C R C N N R N R R R H H NH2 Tertiary amine—good HBA Amide—N acts as poor HBA Aniline—N acts as poor HBA FIGURE 1.11 Comparison of different nitrogen containing functional groups as hydrogen bond acceptors (HBAs). 8 Chapter 1 Drugs and drug targets: an overview O O O O molecules, such as aliphatic substituents or the overall C C C C carbon skeleton. The electronic distribution in neutral, O R RHN R R R RO R non-polar regions is never totally even or symmetrical, Increasing strength of carbonyl oxygen as a hydrogen bond acceptor and there are always transient areas of high and low elec- tron densities leading to temporary dipoles. The dipoles FIGURE 1.12 Comparison of carbonyl oxygens as in one molecule can induce dipoles in a neighbouring hydrogen bond acceptors. molecule, leading to weak interactions between the two molecules (Fig. 1.14). Thus, an area of high electron den- R R H sity on one molecule can have an attraction for an area of H low electron density on another molecule. The strength N N N R R R H R H of these interactions falls off rapidly the further the two molecules are apart, decreasing to the seventh power of Aminium ion Secondary and the separation. Therefore, the drug has to be close to the (stronger HBD) primary amines target binding site before the interactions become impor- FIGURE 1.13 Comparison of hydrogen bond donors tant. Van der Waals interactions are also referred to as (HBDs). London forces. Although the interactions are individu- ally weak, there may be many such interactions between of the nitrogen can interact with neighbouring π systems a drug and its target, and so the overall contribution of to form various resonance structures. As a result, it is less van der Waals interactions is often crucial to binding. likely to take part in a hydrogen bond. Hydrophobic forces are also important when the non- Similarly, the ability of a carbonyl group to act as a polar regions of molecules interact (section 1.3.6). hydrogen bond acceptor varies depending on the func- tional group involved (Fig. 1.12). 1.3.4 Dipole–dipole and ion–dipole It has also been observed that an sp3 hybridized oxy- gen atom linked to an sp2 carbon atom rarely acts as an interactions HBA. This includes the alkoxy oxygen of esters and the Many molecules have a permanent dipole moment result- oxygen atom present in aromatic ethers or furans. ing from the different electronegativities of the atoms and Good hydrogen bond donors contain an electron- functional groups present. For example, a ketone has a deficient proton linked to oxygen or nitrogen. The more dipole moment due to the different electronegativities of electron-deficient the proton, the better it will act as a the carbon and oxygen making up the carbonyl bond. The hydrogen bond donor. For example, a proton attached binding site also contains functional groups, so it is inevi- to a positively charged nitrogen atom acts as a stronger table that it too will have various local dipole moments. hydrogen bond donor than the proton of a primary or It is possible for the dipole moments of the drug and the secondary amine (Fig. 1.13). Because the nitrogen is binding site to interact as a drug approaches, aligning the charged, it has a greater pull on the electrons surrounding drug such that the dipole moments are parallel and in it, making attached protons even more electron-deficient. opposite directions (Fig. 1.15). If this positions the drug such that other intermolecular interactions can take place between it and the target, the alignment is benefi- 1.3.3 Van der Waals interactions cial to both binding and activity. If not, then binding and Van der Waals interactions are very weak interactions activity may be weakened. An example of such an effect that are typically 2–4 kJ mol−1 in strength. They involve can be found in antiulcer drugs (section 25.2.8.3). The interactions between hydrophobic regions of different strength of dipole–dipole interactions reduces with the Drug Drug Drug δ+ δ– δ+ δ– Binding site Binding site δ– δ+ Binding site Hydrophobic regions Transient dipole on drug Induced dipole on target and van der Waals interaction FIGURE 1.14 Van der Waals interactions between hydrophobic regions of a drug and a binding site.  Intermolecular bonding forces 9 δ− O Dipole moment δ+ C R R Localized dipole moment R O C R Binding site Binding site FIGURE 1.15 Dipole–dipole interactions between a drug and a binding site. cube of the distance between the two dipoles. This means the positive charge of the quaternary ammonium group that dipole–dipole interactions fall away more quickly distorts the π electron cloud of the aromatic ring to pro- with distance than electrostatic interactions, but less duce a dipole moment where the face of the aromatic quickly than van der Waals interactions. ring is electron-rich and the edges are electron-deficient An ion–dipole interaction is where a charged or ionic (Fig. 1.17). This is also called a cation-pi interaction. An group in one molecule interacts with a dipole in a sec- important neurotransmitter called acetylcholine forms ond molecule (Fig. 1.16). This is stronger than a dipole– this type of interaction with its binding site (section 22.5). dipole interaction and falls off less rapidly with separa- tion (decreasing relative to the square of the separation). 1.3.5 Repulsive interactions Interactions involving an induced dipole moment have been proposed. There is evidence that an aromatic So far we have concentrated on attractive forces, which ring can interact with an ionic group such as a quater- increase in strength the closer the molecules approach nary ammonium ion. Such an interaction is feasible if each other. Repulsive interactions are also important. R O δ− C δ+ R O R O δ− C O C δ+ H3N R Binding site Binding site FIGURE 1.16 Ion–dipole interactions between a drug and a binding site. + R NR3 δ+ + R NR3 δ− Binding site Binding site FIGURE 1.17 Induced dipole interaction between an alkylammonium ion and an aromatic ring. 10 Chapter 1 Drugs and drug targets: an overview H O H O H H H O O O C H C R R H R R O H O H O O H O H C R R Binding site Binding site Binding site Desolvation—energy penalty Binding—energy stabilization FIGURE 1.18 Desolvation of a drug and its target binding site prior to binding. Drug Drug Drug Hydrophobic Drug regions Binding Water Binding site Binding site Structured water layer Unstructured water round hydrophobic regions increase in entropy FIGURE 1.19 Hydrophobic interactions. Otherwise, there would be nothing to stop molecules try- Sometimes polar groups are added to a drug to ing to merge with each other! If molecules come too close, increase its water solubility. If this is the case, it is impor- their molecular orbitals start to overlap and this results tant that such groups are positioned in such a way that in repulsion. Other forms of repulsion are related to the they protrude from the binding site when the drug binds; types of groups present in both molecules. For example, in other words, they are solvent-accessible or solvent- two charged groups of identical charge are repelled. exposed. In this way, the water that solvates this highly polar group does not have to be stripped away and there 1.3.6 The role of water and hydrophobic is no energy penalty when the drug binds to its target (see section 21.6.2.1 and Case study 5). interactions It is not possible for water to solvate the non-polar or A crucial feature that is often overlooked when consider- hydrophobic regions of a drug or its target binding site. ing the interaction of a drug with its target is the role of Instead, the surrounding water molecules form stronger- water. The macromolecular targets in the body exist in an than-usual interactions with each other, resulting in a aqueous environment and the drug has to travel through more ordered layer of water next to the non-polar surface. that environment in order to reach its target; therefore, This represents a negative entropy due to the increase in both the drug and the macromolecule are solvated with order. When the hydrophobic region of a drug interacts water molecules before they meet each other. The water with a hydrophobic region of a binding site, these water molecules surrounding the drug and the target bind- molecules are freed and become less ordered (Fig. 1.19). ing site have to be stripped away before the interactions This leads to an increase in entropy and a gain in binding described above can take place (Fig. 1.18). This requires energy.* The interactions involved are small at 0.1–0.2 kJ energy and if the energy required to desolvate both the mol−1 for each Å2 of hydrophobic surface, but overall they drug and the binding site is greater than the stabilization can be substantial. Sometimes, a hydrophobic region in energy gained by the binding interactions, then the drug the drug may not be sufficiently close to a hydrophobic may be ineffective. In certain cases, it has even proved beneficial to remove a polar binding group from a drug * The free energy gained by binding (ΔG) is related to the change in in order to lower its energy of desolvation. For example, entropy (ΔS) by the equation ΔG = ΔH−TΔS. If entropy increases, ΔS this was carried out during the development of the anti- is positive, which makes ΔG more negative. The more negative ΔG is, viral drug ritonavir (section 20.7.4.4). the more likely binding will take place.  Classification of drugs 11 region in the binding site and water may be trapped Hydrogen bonds occur between an electron-rich heteroatom between the two surfaces. The entropy increase is not so and an electron-deficient hydrogen. substantial in that case and there is a benefit in designing The functional group providing the hydrogen for a hydro- a better drug that fits more snugly. gen bond is called the hydrogen bond donor. The functional group that interacts with the hydrogen in a hydrogen bond is called the hydrogen bond acceptor. 1.4 Pharmacokinetic issues and Van der Waals interactions take place between non-polar regions of molecules and are caused by transient dipole– medicines dipole interactions. Ion–dipole and dipole–dipole interactions are a weak form of Pharmacodynamics is the study of how a drug binds to its electrostatic interaction. target binding site and produces a pharmacological effect. However, a drug capable of binding to a particular target Hydrophobic interactions involve the displacement of is not necessarily going to be useful as a clinical agent or ordered layers of water molecules which surround hydropho- medicine. For that to be the case, the drug not only has bic regions of molecules. The resulting increase in entropy to bind to its target, it has to reach it in the first place. For contributes to the overall binding energy. an orally administered drug, that involves a long journey Polar groups have to be desolvated before intermolecular with many hazards to be overcome. The drug has to sur- interactions take place. This results in an energy penalty. vive stomach acids then digestive enzymes in the intes- The pharmacokinetics of a drug relate to its absorption, dis- tine. It has to be absorbed from the gut into the blood tribution, metabolism, and excretion in the body. supply and then it has to survive the liver where enzymes try to destroy it (drug metabolism). It has to be distrib- uted round the body and not get mopped up by fat tis- sue. It should not be excreted too rapidly or else frequent 1.5 Classification of drugs doses will be required to maintain activity. However, it should not be excreted too slowly or its effects could lin- There are four main ways in which drugs might be clas- ger on longer than required. The study of how a drug is sified or grouped. absorbed, distributed, metabolized, and excreted (known By pharmacological effect Drugs can be classified as ADME in the pharmaceutical industry) is called phar- depending on the biological or pharmacological effect macokinetics. Pharmacokinetics has sometimes been that they have, for example analgesics, antipsychotics, described as ‘what the body does to the drug’ as opposed antihypertensives, anti-asthmatics, and antibiotics. This to pharmacodynamics—‘what the drug does to the body’. is useful if one wishes to know the full scope of drugs There are many ways in which medicinal chemists available for a certain ailment, but it means that the drugs can design a drug to improve its pharmacokinetic prop- included are numerous and highly varied in structure. erties, but the method by which the drug is formulated This is because there are a large variety of targets at which and administered is just as important. Medicines are not drugs could act in order to produce the desired effect. It just composed of the active pharmaceutical agent. For is therefore not possible to compare different painkillers example, a pill contains a whole range of chemicals that and expect them to look alike or to have some common are present to give structure and stability to the pill, and mechanism of action. also to aid the delivery and breakdown of the pill at the The chapters on antibacterial, antiviral, anticancer, desired part of the gastrointestinal tract. and anti-ulcer drugs (Chapters 19–21 and 25) illustrate the variety of drug structures and mechanisms of action that are possible when drugs are classified according to KEY POINTS their pharmacological effect. Drugs act on molecular targets located in the cell membrane By chemical structure Many drugs which have a com- of cells or within the cells themselves. mon skeleton are grouped together, for example penicil- Drug targets are macromolecules that have a binding site lins, barbiturates, opiates, steroids, and catecholamines. into which the drug fits and binds. In some cases, this is a useful classification as the biologi- cal activity and mechanism of action is the same for the Most drugs bind to their targets by means of intermolecular structures involved, for example the antibiotic activity bonds. of penicillins. However, not all compounds with simi- Pharmacodynamics is the study of how drugs interact with lar chemical structures have the same biological action. their targets and produce a pharmacological effect. For example, steroids share a similar tetracyclic struc- Electrostatic or ionic interactions occur between groups of ture, but they have very different effects in the body. In opposite charge. this text, various groups of structurally related drugs are 12 Chapter 1 Drugs and drug targets: an overview discussed, for example penicillins, cephalosporins, sul- respectively. Finally, if the drugs prove successful and phonamides, opioids, and glucocorticoids (sections 19.4 are marketed as medicines, they are given a proprietary, and 19.5, Chapter 24 and Case study 6). These are exam- brand, or trade name, which only the company can use. ples of compounds with a similar structure and similar For example, the above compounds were marketed as mechanism of action. However, there are exceptions. Fortovase®, Norvir® and Crixivan® respectively (note Most sulphonamides are used as antibacterial agents, that brand names always start with a capital letter and but there are a few which have totally different medical have the symbol R or TM to indicate that they are reg- applications. istered brand names). The proprietary names are also By target system Drugs can be classified according to specific for the preparation or formulation of the drug. whether they affect a certain target system in the body. For example, Fortovase® (or FortovaseTM) is a prepa- An example of a target system is where a neurotransmit- ration containing 200 mg of saquinavir in a gel-filled, ter is synthesized, released from its neuron, interacts with beige-coloured capsule. If the formulation is changed, a protein target, and is either metabolized or reabsorbed then a different name is used. For example, Roche sell into the neuron. This classification is a bit more specific a different preparation of saquinavir called Invirase® than classifying drugs by their overall pharmacological which consists of a brown/green capsule contain- effect. However, there are still several different targets ing 200 mg of saquinavir as the mesylate salt. When a with which drugs could interact in order to interfere with drug’s patent has expired, it is possible for any phar- the system and so the drugs included in this category are maceutical company to produce and sell that drug as likely to be quite varied in structure because of the differ- a generic medicine. However, they are not allowed to ent mechanisms of action that are involved. In Chapters use the trade name used by the company that originally 22 and 23 we look at drugs that act on target systems— invented it. European law requires that generic medi- the cholinergic and the adrenergic system respectively. cines are given a recommended International Non- By target molecule Some drugs are classified accord- proprietary Name (rINN), which is usually identical to ing to the molecular target with which they interact. For the name of the drug. In the UK, such drugs were given example, anticholinesterases (sections 22.12–22.15) are a British Approved Name (BAN), but these have now drugs which act by inhibiting the enzyme acetylcho- been modified to fall in line with rINNs. linesterase. This is a more specific classification as we have As the naming of drugs is progressive, early research now identified the precise target at which the drugs act. In articles in the literature may only use the original letter/ this situation we might expect some structural similarity number code as the name of the drug had not been allo- between the agents involved and a common mechanism cated at the time of publication. of action, although this is not an inviolable assumption. Throughout this text, the names of the active con- However, it is easy to lose the wood for the trees and to stituents are used rather than the trade names, although lose sight of why it is useful to have drugs which switch the trade name may be indicated if it is particularly off a particular enzyme or receptor. For example, it is not well known. For example, it is indicated that sildenafil intuitively obvious why an anticholinesterase agent could is Viagra® and that paclitaxel is Taxol®. If you wish to be useful in treating Alzheimer’s disease or glaucoma. find out the trade name for a particular drug, these are listed in Appendix 6. If you wish to ‘go the other way’, Appendix 7 contains trade names and directs you to the 1.6 Naming of drugs and medicines relevant compound name. Only those drugs covered in the text are included and if you cannot find the drug you The vast majority of chemicals that are synthesized are looking for, you should refer to other textbooks or in medicinal chemistry research never make it to the formularies such as the British National Formulary (see market place and it would be impractical to name ‘General further reading’). them all. Instead, research groups label them with a KEY POINTS code which usually consists of letters and numbers. The letters are specific to the research group undertak- Drugs can be classified by their pharmacological effect, their ing the work and the number is specific for the com- chemical structure, their effect on a target system, or their pound. Thus, Ro31-8959, ABT-538, and MK-639 were effect on a target structure. compounds prepared by Roche, Abbott, and Merck Clinically useful drugs have a trade (or brand) name, as well pharmaceuticals respectively. If the compounds con- as a recommended international non-proprietary name. cerned show promise as therapeutic drugs they are Most structures produced during the development of a new taken into development and named. For example, the drug are not considered for the clinic. They are identified by above compounds showed promise as anti-HIV drugs simple codes that are specific to each research group. and were named saquinavir, ritonavir, and indinavir  Questions 13 QUESTIONS 1. The hormone adrenaline interacts with proteins located on 2. Valinomycin is an antibiotic which is able to transport the surface of cells and does not cross the cell membrane. ions across cell membranes and disrupt the ionic balance However, larger steroid molecules, such as estrone, cross of the cell. Find out the structure of valinomycin and cell membranes and interact with proteins located in explain why it is able to carry out this task. the cell nucleus. Why is a large steroid molecule able to 3. Archaea are microorganisms that can survive in extreme cross the cell membrane when a smaller molecule such as environments, such as high temperature, low pH, or high adrenaline cannot? salt concentrations. It is observed that the cell membrane phospholipids in these organisms (see Structure I below) CH3 O OH are markedly different from those in eukaryotic cell HO NHMe membranes. What differences are present and what function might they serve? HO HO Adrenaline Estrone O O P OCH2CH2NH3 O O H O Structure I 4. Teicoplanin is an antibiotic which ‘caps’ the building 7. Most unsaturated alkyl chains in phospholipids are cis blocks used in the construction of the bacterial cell wall rather than trans. Consider the cis-unsaturated alkyl such that they cannot be linked up. The cell wall is a chain in the phospholipid shown in Fig. 1.2. Redraw barrier surrounding the bacterial cell membrane and the this chain to give a better representation of its shape building blocks are anchored to the outside of this cell and compare it with the shape of its trans-isomer. What membrane prior to their incorporation into the cell wall. conclusions can you make regarding the packing of such Teicoplanin contains a very long alkyl substituent which chains in the cell membrane and the effect on membrane plays no role in the capping mechanism. However, if this fluidity? substituent is absent, activity drops. What role do you 8. The relative strength of carbonyl oxygens as hydrogen think this alkyl substituent might serve? bond acceptors is shown in Fig. 1.12. Suggest why the 5. The Ras protein is an important protein in signalling order is as shown. processes within the cell. It exists freely in the cell 9. Consider the structures of adrenaline, estrone, and cytoplasm, but must become anchored to the inner surface cholesterol and suggest what kind of intermolecular of the cell membrane in order to carry out its function. interactions are possible for these molecules and where What kind of modification to the protein might take place they occur. to allow this to happen? 10. Using the index and Appendix 6, identify the structures 6. Cholesterol is an important constituent of eukaryotic cell and trade names for the following drugs—amoxicillin, membranes and affects the fluidity of the membrane. ranitidine, gefitinib, and atracurium. Consider the structure of cholesterol (shown below) and suggest how it might be orientated in the membrane. H3C H CH3 CH3 H CH3 CH3 HO Cholesterol 14 Chapter 1 Drugs and drug targets: an overview FURTHER READING Hansch, C., Sammes, P. G., and Taylor, J. B. (eds) (1990) Meyer, E. G., Botos, I., Scapozza, L., and Zhang, D. Classification of drugs. Comprehensive Medicinal Chemistry, (1995) Backward binding and other structural Vol. 1, Chapter 3.1. Pergamon Press, ISBN 0-08-037057-8. surprises. Perspectives in Drug Discovery and Design Howard, J. A. K., Hoy, V. J., O’Hagan, D., and Smith, G. T. 3, 168–195. (1996) How good is fluorine as a hydrogen bond acceptor? Page, C., Curtis, M., Sutter, M., Walker, M., and Hoffman, B. Tetrahedron 52, 12613–12622. (2002) Drug names and drug classification systems. Jeffrey, G. A. (1991) Hydrogen Bonding in Biological Integrated Pharmacology, 2nd edn, Chapter 2. Mosby, Structures. Springer-Verlag, London. St Louis, MO. Kubinyi, H. (2001) Hydrogen bonding: The last mystery in drug design? In: Testa, B. (ed.) Pharmacokinetic Titles for general further reading are listed on p.763. Optimisation in Drug Research. Wiley, 513–24. Mann, J. (1992) Murder, Magic, and Medicine, Chapter 1. Oxford University Press, Oxford.