R

Kanamycin Amikacin

Tobramycin Dibekacin

OH OH

NH2 NH2

OH OH

OH OH

OH H

FIGURE 25.11 Kanamycin and related compounds.

gentamicins A, B, and C, from which the C component is isolated. Sisomicin was isolated in 1970 from Micromonospora inyoensis and netilmicin is obtained by the ethylation of sisomicin.

Another aminoglycoside that was obtained by partial synthesis is amikacin, where a L-2-hydroxy-4-aminobutyryl group was introduced in the C1 amino group of the deoxystreptamine ring of kanamycin (1972). The increased use of the aminoglycosides for the treatment of infections with Gram-negative bacteria has led to the development of strains resistant to these antibiotics (Figure 25.12).

H3C H3CHN

O-H2N

O-H2N

Gentamicin

Gentamicin

H3C CH3NH

R3HN

FIGURE 25.12 Gentamicin and derivatives.

Ci-C

NHCH3

R3HN

FIGURE 25.12 Gentamicin and derivatives.

Sisomicin Netilmicin

'CHb

CH3HN

CH3HN

Spectinomycin

Spectinomycin ri

NHCOCHCl

Ri

R,

NO,

-H

Chloramphenicol

NO,

-CO^MCHB

Palmitate

NO,

-COCT^COONa

Hemisuccinate

so,ch3

-H

Thiamphenicol

so,ch3

-COC^NH^HCl

Glycinate

FIGURE 25.13 Spectinomycin, chloramphenicol, and thiamphenicol.

Gentamicin contains fewer groups that may react with these enzymes. The introduction of the 2-hydroxy-4-amino group in amikacin protects many groups against these enzymes, while maintaining the activity of the parent molecule. Tobramycin, which was obtained from Streptomyces tenebrarius in 1968, is also less susceptible because one hydroxy group is replaced by hydrogen.

A special product is spectinomycin, which was isolated in 1961 from Streptomyces spectabilis. It is a broad-spectrum antibiotic with a moderate activity. It is used for the treatment of gonorrhea (Figure 25.13).

25.5.1.2 Tetracyclines

The first tetracycline, chlortetracycline, was discovered in 1948 in a culture of Streptomyces aureofaciens. Oxytetracycline was isolated somewhat later (1950) from Streptomyces rimosus. The structure was studied in the laboratories of Lederle (Boothe et al.) and Pfizer (Hochstein et al.) in collaboration with Woodward at Harvard University. The full structure was published in 1952 but complete stereochemistry was obtained later from x-ray diffraction analysis. During these studies, it was found that the removal of chlorine from chlortetracycline by hydrogenolysis led to an active product, tetracycline. In other laboratories, it was shown that tetracycline could be produced by fermentation of a medium poor in chloride using an appropriate strain, e.g., S. alboniger, S. viridifaciens, etc.

The tetracyclines derive their name from the tetracyclic ring system, which is octahydronaph-thacene. They have three ionizable groups, on C3, C4, and the dihydroxy ketone system (C10-C12). The tetracyclines are often used in the form of the hydrochloride, but the tetracycline bases are also used. The C4. dimethylamino-group may epimerize and these epimers are almost inactive. At pH values between 4 and 7, mixtures of normal and epitetracycline are formed.

In acid medium, the C6 hydroxy group and C5 hydrogen are removed in the form of water and anhydrotetracyclines are found. For this reason demeclocyline, which has a C6 secondary hydroxyl group instead of a tertiary one, is more stable. This product was obtained in 1957 using a mutant strain of S. aureofaciens. Chemical manipulations of oxytetracycline led to the production of metacycline. Hydrogenation of metacycline under suitable conditions, gave doxycycline. It should be noted that the C6 methyl group should have the a-configuration as in oxytetracycline, because the C6 epimer is less active. Doxycycline is very stable (no C6-OH group) and has a high lipophilic character. It is more completely absorbed after oral administration. Minocycline was described in 1972 and is prepared by the chemical treatment of 6-deoxy-6-demethyltetracycline.

The tetracyclines are true broad-spectrum antibiotics. They are active against a wide range of Gram-positive and Gram-negative bacteria, spirochetes, mycoplasmas, rickettsiae, and chlamydia.

The in vitro activities of the different tetracyclines are very similar. Only the greater activity of minocycline against some Gram-positive bacteria like staphylococci and streptococci should be noted (Figure 25.14).

H

OH

CH3

H

Tetracycline

Cl

OH

CH3

H

Chlortetracycline

H

OH

CH3

OH

Oxytetracycline

Cl

OH

H

H

Demeclocycline

H

= CH2

OH

Metacycline

H

H

CH3

OH

Doxycycline

N(CH3)2

H

H

H

Minocycline

FIGURE 25.14 Tetracyclines.

25.5.2 Inhibitors of the 50 S Ribosomal Subunit

25.5.2.1 Chloramphenicol

The first broad-spectrum antibiotic was chloramphenicol, which was isolated in 1947 from Streptomyces venezuelae. Its chemical structure was soon established and in 1949 a synthesis was described. The commercial production always has been by the synthetic route. Of the four possible diastereoisomers, only the R, R isomer is active and is separated during the synthesis.

Many derivatives of chloramphenicol were prepared but only the sulfomethyl analogue, thiam-phenicol, has come into clinical use. It is generally less active than chloramphenicol. The glycinate ester is used as a prodrug for injections. Chloramphenicol has a moderate activity against Grampositive and Gram-negative bacteria. It is not recommended for treatment of these infections, because of the occurrence of serious toxic reactions in the blood (aplastic anemia, thrombocytopenia). It is still used in the treatment of typhus and meningitis caused by Haemophilus influenzae.

25.5.2.2 Macrolides

The macrolide antibiotics have in common (a) a large lactone ring (hence the name macrolide); (b) a glycosidically linked aminosugar (sometimes two), and (c) usually a desoxysugar. The lactone ring may contain 12 (macrolides not used in medicine), 14 (erythromycin, oleandomycin), and 16 atoms (leucomycin, spiramycin, tylosin).

The first clinical useful macrolide was erythromycin, isolated from a culture of Streptomyces erythreus (1952). The structure was determined by chemical methods (1954-1957) and the stereochemistry and conformation by x-ray diffraction and NMR. Erythromycin is inactivated by acid.

Clarithromycin, where the C6-hydroxy group is replaced by a methoxy group and roxithromycin, where the ketone group is under the form of an oxime-ether is more acid-stable (Figure 25.15).

The 9-position of erythromycin has been changed more dramatically in dirithromycin and azithromycin. Their spectra are comparable to that of erythromycin itself. Azithromycin has a longer half-life. Recently, telithromycin was introduced as a semisynthetic derivative of erythromy-cin. It is active a.o. against S. pneumonia, b-hemolytic streptococci, L. pneumophila, Chlamydia pneumoniae, and Mycoplasma pneumoniae (Figure 25.16).

Oleandomycin was isolated in 1955 by Sobin et al. from Streptomyces antibioticus, It is administered usually as the triacetyl derivative, which gives higher blood levels.

H3C HO

D-Desosamine N(CH3)2

D-Desosamine N(CH3)2

H3C HO

H3C OCH3 R1 R2 Erythromycin H = O

Roxithromycin H = N— O — CH2CH2 — OCH3 Clarithromycin CH3 ^=O

H3C OCH3 R1 R2 Erythromycin H = O

Roxithromycin H = N— O — CH2CH2 — OCH3 Clarithromycin CH3 ^=O

h3c'

D-Desosamine

D-Desosamine

OCH3

L-Oleandrose o' y o

OCH3

L-Oleandrose

Oleandomycin R = H

Troleandomycin R = COCH3

FIGURE 25.15 Macrolides.

FIGURE 25.16 C7-C12 fragments of dirithromycin and azithromycin.

FIGURE 25.16 C7-C12 fragments of dirithromycin and azithromycin.

Erythromycin is very active against Gram-positive bacteria. Oleandomycin has a similar spectrum, but the MIC are generally higher.

Spiramycin and leucomycin are macrolides with a more limited use. Spiramycin was discovered in S. ambofaciens (1955). Besides the main component I, it contains some components II (max. 15%) and III (max. 10%).

Another active macrolide is tylosin. Its application is restricted to veterinary medicine.

25.5.2.3 Lincomycin, Clindamycin

Lincomycin is also a basic antibiotic isolated in 1962 from Streptomyces lincolnensis. The basic group is in the proline part of the molecule and the sugar moiety contains a methylmercapto group. In 1967, it was shown that replacement of a hydroxy group by chlorine, with inversion of configuration, resulted in a product clindamycin, with improved absorption and higher serum levels. Both antibiotics are active against Gram-positive bacteria, with a spectrum similar to that of erythromy-cin. Side effects are diarrhea and occasionally serious pseudomembranous colitis, which is caused by an overgrowth of clindamycin-resistant strains of Clostridium difficile (Figure 25.17).

25.5.2.4 Fusidic Acid

Fusidic acid (Figure 25.6) was isolated from Fusidium coccineum in 1962. It has a unique steroid type (fusidane) structure. Cephalosporin Pj has a similar structure. Fusidic acid is active against Gram-positive bacteria and Gram-negative cocci. Resistant strains rapidly emerge. Because of this observation, its use is limited.

25.6 CELL WALLS OF BACTERIA

Most prokaryotic cells are surrounded by a cell wall that is responsible for their shape and allows bacteria to live in a hypotonic environment without bursting. In 1884, C. Gram discovered that some bacteria retained crystal violet-iodine complex after washing with alcohol (Gram-positive) and others did not (Gram-negative).

Gram-positive cells are surrounded by a cytoplasmic membrane and a thick cell wall consisting of peptidoglycan to which are linked polyol phosphate polymers called teichoic acids. Gram-negative bacteria have a much thinner cell wall consisting of peptidoglycan and associated proteins, and this cell wall is surrounded by an outer membrane comprising of lipid, lipopolysaccharide, and protein. The osmotic pressure in the cytoplasm of Gram-positive bacteria (±20 atm) is higher than that of in Gram-negative (±5 atm).

Peptidoglycan is an alternating polymer of N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM), which are cross-linked by a short peptide bridge, and which is 200-250 Â thick in Gram-positive bacteria. Peptidoglycan forms an enormous bag shaped molecule, also called "murein sacculus" (Latin murus: wall), which surrounds the entire cell.

NAM is the 3-0-D-lactylether of N-acetylglucosamine. NAG and NAM are linked by b(1-4) glycosidic bonds and form a linear structure as in cellulose (glucose units) and in chitin

CH3 ch2cho

n(ch3)2

(ch3)2n

CH3 ch2cho

n(ch3)2

Mycarose

-COCH2CH(CH3)2

Mycarose

Forosamine

Forosamine

Spiramycin I Spiramycin II Spiramycin III Leucomycin A,

COCH3 COCH2CH3

-COCH2CH(CH3)2

S CH3

S CH3

Lincomycin Rj = OH Clindamycin Rj = H

FIGURE 25.17 Macrolides and lincomycin (derivatives).

(N-acetylglycosamine units). The carboxyl group of NAM is linked to a short peptide, which forms the bridge with another NAG-NAM strand.

One of the important new targets to develop antibiotics is the transglycosylase reaction, responsible for the polymerization of the disaccharide units. During the transglycosylase reaction, the configuration of Q is changed from a to p. Moenomycin A, active against Gram-positive bacteria, is a transglycosylase inhibitor (Figure 25.18).

The formation of the linkage between two peptide ends is catalyzed by a transpeptidase bound to the outside of the cytoplasmic membrane.

This reaction regulates the degree of peptidoglycan cross-linking. In Staphylococcus aureus, 90% of the peptide chains are involved in cross-links, whereas in Gram-positive and Gram-negative bacilli only 20%-50% of the strands are cross-linked.

Vancomycin kills bacteria by targeting lipid II. Lipid II is the target of several other classes of natural products like lantibiotics, ramoplanin, and mannopeptimycins. Nisin that acts through a lipid-II-dependent targeted pore formation mechanism is an example of a lantibiotic. Vancomycin and teicoplanin dissociate with the acyl-D-Ala-D-Ala terminus of the growing peptidoglycan chain. Both compounds are active against Gram-positive bacteria. Resistance against vancomycin is observed when the D-Ala-D-Ala terminus is changed to D-Ala-D-Lac. Nisin is active against vanco-mycin resistant bacteria because it does not interact with the amino acids of the pentapeptide chain (Figure 25.19).

O OC55H89

D-Ala-D-Ala-Lys-D-Glu-Ala

D-Ala-D-Ala-Lys-D-Glu-Ala p

-o" noc55h89

O OC55H89

Membrane

CO HO I NH

OH CONH,

FIGURE 25.18 Transglycosylation step and structure of moenomycin A.

(B) Moenomycin A

FIGURE 25.18 Transglycosylation step and structure of moenomycin A.

H OI

H OI

D-Ala-D-Ala

D-Ala-D-Lac

D-Ala-D-Lac

FIGURE 25.19 Binding of vancomycin at D-ALa-D-Ala and D-Ala-D-Lac.

b-Lactam antibiotics inhibit transpeptidase and carboxypeptidase. In this reaction, the b-lactam ring is opened and the serine of catalytic part of the enzyme is acylated. The inhibition of the cross-linking reaction yields a poorly structured cell wall and results in the lysis of the cell. This explains the early observation that penicillin affects only growing bacteria.

From 1972 onward, several investigators could show, using radioactive penicillin and separation techniques, that membranes of bacteria contained several penicillin-binding proteins (PBPs). Differences in susceptibility of bacteria to different b-lactams may be explained by the amounts of the different PBPs and their affinity for these antibiotics. The PBP of lower molecular mass are monofunctional carboxy- and endopeptidases, transpeptidases, and b-lactamase. The higher molecular mass PBPs are multimodular containing a transpeptidase and, for example, a transglyco-sylase. It seems that inhibition of at least two PBPs is required for efficient killing by b-lactams.

In the periplasmic space (between cytoplasmic membrane and outer membrane), several enzymes are present, e.g., b -lactamases (in all Gram-negative bacteria), enzymes that acetylate chloram-phenicol, adenylate streptomycin, etc. and also proteins responsible for the transport of sugars and other nutrients.

In Gram-negative bacteria, antibiotics have to pass through the porins. This permeation is easiest for polar molecules. A second factor in their activity is the resistance to b -lactamase. A third factor, both in Gram-positive and Gram-negative bacteria is the affinity for PBP. There are marked differences in this affinity for different penicillins and cephalosporins. The minimum inhibitory concentration (MIC) that measures the in vitro activity of an antibiotic is the result of a series of different factors.

25.7 MEMBRANES

The cytoplasmic membrane of bacteria is also a lipoprotein structure. The major phospholipid is phosphatidylethanolamine. Several proteins (also enzymes) are located in and around this membrane. Polymyxin and colistin interact with the cell membrane. The binding of the drug involves the phosphate groups of the phospholipid. According to a mechanism similar to that of the quaternary ammonium detergents, the fatty acid tail penetrates into the hydrocarbon part of the phospholipid, while the cyclic peptide containing the free amino groups interacts with the phosphate groups. This disruption of the membrane structure brings about a loss of their permeability barrier property. Biochemical functions like respiration, nucleic acid and protein synthesis are perturbed. Tyrocidine that does not have a detergent-like structure nevertheless has a similar effect.

Ionophores cause the loss of essential monovalent cations (K+) because of specific changes in the permeability of the membrane. The polyethers act as carriers, by providing lipid solubility of the transported cations. Gramicidin, which is a linear peptide, probably adopts a helical conformation and forms a hydrophobic channel of the ions.

25.8 NUCLEIC ACID SYNTHESIS

The planar phenoxazone ring of actinomycin intercalates at the level of GpC sequences in DNA. This intercalation partially unwinds the DNA helix and inhibits the use of DNA for replication and transcription. The anthracycline antibiotics have a more complex mode of action: they intercalate in DNA, they have alkylating properties, they inhibit the action of topoisomerase II and could give rise to hydroxyl radicals that damage DNA. Several antitumoral antibiotics like daunomycin and bleomycin may break strands of DNA and give rise to cross-linking. Rifampicin inhibits RNA polymerase by directly binding to the enzyme in a noncovalent manner. The drug does not inhibit transcription once it has begun, but prevents the initiation of the transcription.

A molecule of DNA consists of two linear strands intertwined to form a double helix. Those strands form often a ring. Such a relaxed bacterial DNA is too long to fit inside a bacterial cell.

Supercoiling is essential for housing inside the cell and strand unwinding is necessary for replication and transcription.

Topoisomerases are enzymes that convert DNA from one topological form to another. The enzyme hydrolyses the phosphodiester bond of DNA backbone, making use of tyrosine residues in the protein, allows the supercoiled DNA to pass into the relaxed form and reseals the strands.

Topoisomerase I cuts a single strand of the double helix, topoisomerase II cuts two strands simultaneously. DNA gyrase, discovered by Gellert in 1976, is a topoisomerase II, which occurs only in prokaryotes. It is able to supercoil a relaxed DNA ring (reaction A). ATP is required as an energy source in this process. Quinolones inhibit the catalytic activity of DNA gyrase and stabilize the DNA cut. This means that the higher the topoisomerase activity in a cell, the more active the qui-nolones will be. DNA gyrase consists of two A subunits and two B subunits and the A subunits are involved in cleavage and annealing of the DNA strands. The targeting of the enzymes (gyrase A, a subunit of topoisomerase IV) by fluoroquinolines is organism- and compound-specific.

25.9 PROTEIN SYNTHESIS

Ribosomes are cellular particles, 200-500 A in diameter. About 1800 are present per bacterial cell, where they are bound to the cytoplasmic membrane. All ribosomes can dissociate into a small and a large subunit. In prokaryotes, the 70 S ribosome (sedimentation coefficient 70 S) consists of a 30 and a 50 S subunit. The 30 S subunit contains a 16 S RNA molecule, the 50 S subunit a 23 and a 5 S RNA molecule. The ribosomes of eukaryotic cells are larger (80 S) with 60 and 40 S subunits. Several ribosomes simultaneously translate mRNA. The complex of mRNA and several ribosomes is called as a polyribosome. Several antibiotics interfere with protein synthesis at the level of the ribosome. The macrolides (for example erythromycin) bind to the 50 S subunit and inhibit the translocation reaction. The aminoglycoside (for example streptomycin) interferes with the initiation step of protein synthesis and also induces miscoding during protein synthesis. They interact with the 30 S subunit. The binding mode of aminoglycosides to the A site of the 16 S ribosomal RNA has been determined using x-ray diffraction studies and is based on electrostatic interactions and direct and water-mediated hydrogen bonds. Aminoglycosides stabilize a conformation of the aminoacyl-tRNA decoding site that normally occurs when the tRNA-mRNA complex is bound. The ribosome now is unable to discriminate between cognate and noncognate tRNA-mRNA duplex.

Tetracyclines bind to the 30 S subunit and inhibit the binding of aminoacyl-tRNA at the A-site of the ribosome. Chloramfemicol is an inhibitor of the peptidyl transferase activity of the 50 S subunit and releases short oligopeptidyl-tRNA. Fusidic acid stabilizes the normally unstable ribosome-elongation factor G-GTP complex and inhibits translocation.

Puromycin is an antibiotic that has been isolated from S. alboniger in 1953 but that is not used in the clinic. It has been very useful in the study of the protein synthesis. It resembles the amino-acyl-adenosine part of aminoacyl-tRNA. It binds to the A-site in the ribosome in the place of an aminoacyl-tRNA. The amino group of puromycin forms a peptide bond with the peptide, a reaction catalyzed by peptidyl transferase. The peptidylpuromycin is then released from the ribosome and thus causes premature chain termination.

25.10 NEW DEVELOPMENTS IN ANTIBACTERIAL RESEARCH

Since the last new structural class of antibiotics has been discovered (quinolons), only few really new antibiotics have been approved, i.e., linezolid, daptomycin, tigecycline, and retapamulin. Tigecycline is a glycylcycline that is active against Gram-positive and Gram-negative bacteria. It inhibits protein synthesis. Daptomycin is used against Gram-positive infections, including resistant pathogens such as MRSA (methycillin-resistant Staphylococcus aureus), VRE (vancomycin-resistant enterococci), and PRSP (penicillin-resistant Streptococcus pneumoniae). It is a cyclic lipopeptide that originates from Streptomyces roseosporus, discovered at Eli Lilly in the early 1980s. It has a unique mode of action, as it disrupts several functions of the bacterial plasma membrane without penetrating into the cytoplasm. The insertion of daptomycin into the cytoplasmic membrane bilayers is calcium-dependent. In the presence of calcium, daptomycin readily forms aggregates. Its concentration in the membrane causes leakage leading to cell death. The oxazolidinones (i.e., linezolid) are active against Gram-positive pathogenic bacteria (including MRSA) and inhibit bacterial translation at the initiation phase of protein synthesis. It binds to the 50 S subunit and inhibits the interaction with the 30 S subunit. Retapamulin is a semisynthetic pleuromutilin, a natural product of the fungi Pleurotus mutilis. It is active against S. aureus and S. pyogenes and used for the treatment of impetigo. Retapamulin inhibits bacterial protein synthesis by binding to the bacterial ribosomal 50 S subunit. Its binding site is different from that of the classical ribosome-binding antibiotics (Figure 25.20).

During the last decennium, successful drug classes, like b-lactams (ceftazoline, ceftobiprole), tetracyclines (tigecycline), macrolides (cetromycin), and trimethoprim (iclaprim) have been modified by introduction of additional target binding sites, so that the compounds become active against resistant strains. Other possibilities to obtain improved antibiotics are the synthesis of hybrids of two antibiotic pharmacophores, the development of multitargeted antibiotics, and the combination therapy.

During the last two decennia, several discoveries and new technologies that could increase the likelihood of identifying new antibiotics or antibiotic targets became available. Examples are combinatorial library synthesis (i.e., the automatic synthesis of complex oligosaccharides), new screening methods, the availability of bacterial genome sequences, a better understanding of the host immune system, natural product screening, the discovery of riboswitches, and the availability of more x-ray structure of bacterial proteins. Despite this, however, the main target for antibiotic development is still not altered and includes DNA replication, cell-wall biosynthesis, ribosomal RNA function, and membrane functions. It seems that the use of other antibacterial targets mainly leads to antibiotics with a narrow spectrum and that targeting multiple enzymes will be needed together with the development of new chemistries (from natural or bioengineering origin). The de novo design of multiple-targeted antibiotics for monotherapy is a difficult process. An alternative is to target functions, essential for infection, such as bacterial virulence factors or disrupting the interactions between the host and the pathogen (with lesser risk to develop antibiotic resistance). Improvement of the treatment of bacterial infections might also be expected when the antibiotic is combined with a compound that inhibits the mechanisms of persistence.

Antibiotic resistance is presently a serious problem in the fight against bacterial infections. Three types of resistance mechanism can be distinguished: (a) natural or intrinsic resistance; (b) mutational

Daptomycin

FIGURE 25.20 Daptomycin, linezolid, and retapamulin.

Daptomycin

FIGURE 25.20 Daptomycin, linezolid, and retapamulin.

resistance; and (c) extrachromosomal acquired resistance, which is disseminated by plasmids or transposons. The first type of resistance can be due to the inaccessibility of the target, the presence of a multidrug efflux system, or due to inactivation of the antibiotic. The mutational resistance, likewise, may be of different origin. This resistance may be due to a reduced permeability or uptake, a metabolic bypass, a modification of the target site, or a repression of the multidrug efflux system. The third type of resistance may be caused by drug inactivation, target site modification, metabolic by-pass, or the efflux system. The existence of multidrug-resistance efflux pumps is the major mechanism of intrinsic and acquired resistance of bacteria against a variety of different antibiotics. The resistance-nodulation-cell-division (RND) family of transporters form a large multiprotein complex that transverse the inner and outer membrane of Gram-negative bacteria through the periplasmic region. Inhibition of the efflux pumps could be used in combination with antibiotics and a variety of such compounds have been identified. It has been observed that antibacterial targets, that give rise to low occurrence of resistance through single-step mutation, are of made of multiple genes or are structures that are synthesized by multiple genes. Antibacterials targeting single enzymes easily give rise to high-level resistance and are best used in combination therapy.

Another important observation is that most bacterial infections contain nonmultiplying bacteria that are resistant to treatment with antimicrobial drugs. They could exist as spores, in a dormant state, or in a clinically latent situation. The best-known example of a clinically latent bacterium is the Mycobacterium tuberculosis. The use of drugs that target nonmultiplying bacteria should result in shorter treatment periods and, hence, a lower level of resistance. Some of the known antibiotics (i.e., penems, nocardicin A, some quinolines, rifampicins) are able to kill some nonmultiplying bacteria.

25.11 CONCLUDING REMARKS

Development of antibiotics is one of the oldest fields in medicinal chemistry and antibiotics have saved uncountable lives of human beings during the last 60 years. It is a research domain that has been neglected during the last two decennia with serious consequences. The bugs are fighting back and they have learned how to defend themselves against their killers. There is an urgent need for new antibacterials with new mode of actions. Likewise, the way of discovery of new antibacterials should be altered. In the past, this was mainly focused on the discovery of inhibitors of bacterial growth. The example of tuberculosis shows that this is not sufficient. The main problem is that the development of new antibiotics is one of the difficult fields of medicinal chemistry. Using leads from nature combined with medicinal chemistry to influence the spectrum and the pharmacokinetics of the natural compounds will remain one of the most important ways to develop new antibiotics.

FURTHER READINGS

E. Breukink and B. de Kruiff. Lipid II as a target for antibiotics. Nat Rev Drug Discov. 5, 321-332, 2006. A.E. Clatworthy, E. Pierson, and D.T. Hung. Targeting virulence: A new paradigm for antimicrobial therapy.

Nat Chem Biol. 3, 541-548, 2007. A. Coates, Y. Hu, R. Bax, and C. Page. The future challenges facing the development of new antimicrobial drugs. Nat. Rev. Drug Discov. 1, 895-910, 2002. O. Lomovskaya, H.I. Zgurskayal, M. Totrov, and W.J. Watkins. Waltzing transporters and 'the dance macabre'

between humans and bacteria. Nat. Rev. Drug Discov. 6, 56-65, 2007. D.J. Payne, M.N. Gwynn, D.J. Holmes, and D.L. Pompliano. Drugs for bad bugs: Confronting the challenges of antibacterial discovery. Nat. Rev. Drug Discov. 6, 29-40, 2007. L.L. Silver. Multi-targeting by monotherapeutic antibacterials. Nat. Rev. Drug Discov. 6, 41-55, 2007. P.A. Smith and F.E. Romesberg. Combating bacteria and drug resistance by inhibiting mechanisms of persistence and adaptation. Nat Chem Biol. 3, 549-556, 2007.

Index aa-tRNA, see Aminoacylated transfer RNA Abatacept protein, 373

Absorption-distribution-metabolism-excretion, 2, 135 ACD database, see Available Chemical Directory database

ACE, see Angiotensin-converting enzyme Acetylcholine (ACh), 265 Acetylcholine binding protein, 20, 195, 244 Acetylcholine-gated ion channels, striated muscle, 209 Acetylcholinesterase (AChE), 65, 266, 269-271 Acetylcholinesterase inhibitors (AChEIs), 265-266, 270 AChBP, see Acetylcholine binding protein Actinomycin, 433

Actinoplanes teichomycelicus., 430

ADHD, see Attention deficit hyperactivity disorder

ADME, see Absorption-distribution-metabolism-excretion

ß-Adrenergic antagonist timolol, usage problem, 142

Agouti-related protein (AGRP), 132

Alemtuzumab, usage, 373

Alimta, 382-384; see also Cancer

Allosteric modulators, 203

Allosteric serotonin reuptake inhibitor (ASRI), 304, 308-310

Alzheimer's disease (AD), 263-266 cholinergic hypothesis, 264-265 diagnosis of, 263 memantine, 265 Amanita muscaria, 9, 272 Amino acid scans, peptide/protein design, 126 Aminoacylated transfer RNA, 66 y-Aminobutyric acid (GABA), 68, 190, 227, 233, 239-240 biosynthesis and metabolism, 241-242 and glutamic acid neurotransmitter systems, 240-241 and glycine transporters, inhibitors, 237-238 receptors and ligands ionotropic, 243-246 ligands differentiating, 248-249 modulatory agents, 246-247 receptor ligands, 247-248 transport, 242-243 y-Aminobutyric acid type A (GABAa) receptor, 44 a-Amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA), 115, 250 4-Aminoquinolines, 347-349; see also Malaria 8-Aminoquinolines, 353; see also Malaria Amitriptyline, 306

AMPA receptor agonists, 253-255; see also Ionotropic glutamate receptor (iGluR) ligands AMPA receptors, modulatory agents, 255-256; see also Ionotropic glutamate receptor (iGluR) ligands Amphetamine, 236 Ampakines, 266

Amyloid plaques, component, 263 Amyloid precursor protein, 263-264 Anabaena flos aquae, 278 Anandamide, biosynthesis, 322 Angiogenesis and blood vessels formation, 379;

see also Cancer Angiotensin-converting enzyme, 9 Anthracyclines, 433

Antibacterial research, developments, 445-447; see also Antibiotics

Antibiotics in bacterial cell wall formation bacitracin, 429-430 P-lactam antibiotics, 420-429 vancomycin, 430 in cytoplasmic membrane polyether antibiotics, 431-432 polymyxin, 431 tyrothricin, 430-431 in nucleic acid synthesis actinomycin and anthracyclines, 433 RNA polymerase inhibition, 433-434 in protein synthesis

30 S ribosomal subunit, inhibitors, 434-439 50 S ribosomal subunit, inhibitors, 440-441 usage, 92-94

Antibody dependant cell-mediated cytotoxicity (ADCC),

364-365 Anticancer agents, usage, 380 alimta, 382-384 gleevec, 388-390 herceptin, 390-391 taxol, 384-385 xeloda, 381-382 zolinza, 385-388 Antidepressant drugs, 304-305; see also Transporter ligands allosteric serotonin reuptake inhibitor, 309-310 first generation drugs, 305-306 serotonin reuptake inhibitors, 306-309 SSRI pharmacophore and SERT homology model, 310-311

Antigen presenting cells (APCs), 360-361 Anti-HBV compounds adefovir dipivoxil, 404-405 entecavir, 406 lamivudine, 404 telbivudine, 406 Antiherpes virus compounds

Cytomegalovirus (CMV) inhibitors cidofovir, 411 fomivirsen, 411-412 foscarnet, 411 ganciclovir, 410 valganciclovir, 411

Herpes simplex virus (HSV) and Varicellazoster virus (VZV) inhibitors acyclovir, 406 brivudin, 409 famciclovir, 407-408 idoxuridine, 408 penciclovir, 407 trifluridine, 408-409 valaciclovir, 406-407 Anti-HIV compounds

Nonnucleoside reverse transcriptase inhibitors (NNRTIs) delavirdine, 400 efavirenz, 400 nevirapine, 399-400 Nucleoside reverse transcriptase inhibitors (NRTIs) abacavir, 397 didanosine, 395-396 emtricitabine, 397 lamivudine, 397 stavudine, 396 zalcitabine, 396 zidovudine, 394-395 Nucleotide reverse transcriptase inhibitors

(NTRTIs), 397-398 Protease inhibitors amprenavir, 402-403 atazanavir, 403 darunavir, 403-404 fosamprenavir, 403 indinavir, 402 lopinavir, 403 nelfinavir, 402 ritonavir, 400-402 saquinavir, 400 tipranavir, 403 viral entry inhibitors, 404 Anti-influenza drugs, 31-33; see also Biostructure-based drug design Anti-influenza virus compounds amantadine, 412-413 oseltamivir, 414 ribavirin, 414-415 rimantadine, 413 zanamivir, 413-414 Antimony, role in medicine, 169 Antipsychotic drugs, 300, 302-303 Antiviral agents, preclinical development, 416 APP, see Amyloid precursor protein Aquifex aeolicus, 228, 310 Aripiprazole, 302 Artemisia annua, 92 Artemisia apiacea, 349 Aspartyl protease, reaction pathway, 175-176 Asymmetric synthesis, usage, 85-87;

see also Drug design ATP-binding cassette (ABC) transporters, 225 Atropa belladonna, 273 Attention deficit hyperactivity disorder, 237 Autocrine stimulation, 378; see also Cancer

Available Chemical Directory database, 50 Azathioprine, 366

Bacillus aerosporus, 431 Bacillus brevis, 430 Bacillus colistinus, 431 Bacillus polymyxa, 431

Bacillus subtilis and bacitracin production, 429;

see also Antibiotics Baclofen, 241 Bacteria cell walls, 441-444 membranes, 444 Bacterial cell wall formation, antibiotics bacitracin, 429-430 P-lactam antibiotics, 420-429 vancomycin, 430 B cell receptor (BCR), 360-361, 372-373 B cells, 361; see also Immune system BCR-ABL, see Breakpoint cluster region-abelson tyrosine kinase oncogene Benadryl, 286

Benign prostatic hyperplasia, 179 Benzodiazepine receptor agonists (BzRAs), 329 determination, 334 limitation, 334-335 structure, 332 Benzodiazepines (BZDs), 44, 240 Benztropine, function, 233-236 Betaine/GABA-transporter-1 (BGT-1), 242 Bioassay-guided fractionation process, 95 Biogenic amine transporters, drugs amphetamine, 236 antidepressants, 236-237 cocaine, benztropine, 233-236 GBR and DAT, 237 Bioinorganic chemistry, 151-152; see also Drug design chelate therapy, 157-159 classification, 153-154 coordination chemistry, 155-157 human body, 154 pharmaceuticals, 159 alkali metals, 160 alkaline earth metals, 160-162 antimony and bismuth, 169-170 copper, silver and gold, 166-169 iron and cobalt, 162-163 platinum and ruthenium, 163-166 zinc, 169 Bioisosteres, usage, 10

Biological active peptides and peptidomimetics drug design, 124 biological function-based design, 132-133 ligand-based design, 125-132 modeling and docking, 133 Biological research, small molecules application, 63-65 generation, 60-63 Biomacromolecules, modification, 65

chemical modification of proteins, 72-73 peptide/protein ligation, 71-72 protein engineering, 66-68 unnatural mutagenesis, 68-70 Biostructure-based drug design, 29-31; see also Drug design anti-influenza drugs, 31-33 experimental and computational methods, 41 fast-acting insulins, 37-41 HIV protease inhibitors, 34-37 Biostructure-based enzyme inhibitor design, 182 of HIV protease inhibitors, 185-188 of protein kinase inhibitors, 183-185 Biosynthetic modifications, natural products, 100-103 Bismuth, role in medicine, 169-170 Bismuth subsalicylate (BSS), 170 Black cohosh, application, 92 Blood-brain barrier (BBB), 270, 272, 277, 334 Bothrops jararaca, 9 BPH, see Benign prostatic hyperplasia Breakpoint cluster region-abelson tyrosine kinase oncogene (BCR-ABL), 183 Brugia malayi, 342 Bungarus multicinctus, 278 Burimamide, usage, 288 Butyrophenones, definition, 301 Butyrylcholinesterase (BuChE), 266, 269

Ca2+-ATPases, 208

CACA, see Cis-4-Aminocrotonic acid

Ca2+ current, cardiac action potential, 209

Cahn-Ingold-Prelog (CIP) system, 77

Calabar bean (Physostigma venenosum), 269

Calcium ion, role in medicine, 160-162

cAMP responsive element-binding protein (CREB), 291

Cancer acquired capabilities, 378-379 anticancer agents, 380 alimta, 382-384 gleevec, 388-390 herceptin, 390-391 taxol, 384-385 xeloda, 381-382 zolinza, 385-388 characteristics, 379-380 malignant cancer, 375-378 Cannabinoid receptors CB1-receptor, 323-324 CB2-receptor, 324 CB1-receptor agonist, 326 CB2-receptor agonist, 326-327 diacylglycerol lipase inhibitors, 327 endocannabinoid system, 321-323 FAAH-inhibitors and anandamide uptake inhibitors, 326 monoacylglycerol lipase inhibitors, 327 therapeutic use and potential, 324-325 Cannabis sativa, 8, 321, 324 Capecitabine, 382

Capillary electrophoresis, usage, 88 Capillary leak syndrome, 371 Carbenicillin, 422 CATALYST, usage, 46-47

Ca 1-family, 218-219; see also Voltage-gated calcium channels

Cav 2-family, 220; see also Voltage-gated calcium channels

Cav 3-family, 220; see also Voltage-gated calcium channels CB1-receptor, 323-324 CB2-receptor, 324 CB1-receptor agonist, 326 CB2-receptor agonist, 326-327 CBS, see Colloidal bismuth subcitrate Cefalexin, 427 Cefaloglycin, 427

Cell-free enzyme preparations, advantages, 87 Cephalosporins, 423-427 Cephalosporium acremonium, 423 CFSE, see Crystal field stabilization energy CFTR protein, 222 Channelopathies, 211

Chelate therapy and bioinorganic chemistry,

157-159 Chemical biology, 59-60 Chemical genetic method, 64-65 Chiral gas chromatography (GC), application, 87 Chirality, definition, 76-78 Chiral stationary phases, 79 Chloramphenicol, 440 Chloride channels, 222 Cholecystokinin (CCK), 128 Choline, chemical structure, 265 Cholinergic synaptic mechanisms, 266 Cholinesterases cholinesterase inhibitors, 266-269 substrate catalysis, 269-271 Chromobacterium violaceum, 429 Chronic myeloid leukemia (CML), 183, 388 Cinchona alkaloids, 353-354; see also Malaria Cis-4-Aminocrotonic acid, 245 Citalopram, 306-308 Clostridium difficile, 430 Clozapine, 302

CNG, see Cyclic nucleotide-gated Cobalt, role in medicine, 163 Cocaine, function, 233-236 Colloidal bismuth subcitrate, 170 Combinatorial chemistry, usage, 60 Competitive inhibitors, 174

Complementarity determining regions (CDRs), 363 Computational methods in biostructure-based drug designs, 41 in drug discovery process, 43 ffl-Conotoxin MVIIA, 220 Contrast-to-noise ratio (CNR), 110 Conventional imaging, 109-110 Coordination chemistry and bioinorganic chemistry, 155-157

Copper, role in medicine, 166-168

Crystal field stabilization energy, 157 CSPs, see Chiral stationary phases Cutaneous T-cell lymphoma (CTCL), 387 Cyclic nucleotide-gated, 212 Cyclophosphamide, 366-367 Cyclosporine A, 366 Cyclothiazide (CTZ), 255, 261 Cystic fibrosis, 211 Cytidine deaminase (CyD), 382 Cytokines interferons (IFN), 369-370 interleukins (IL), 370-372 tumor necrosis factor (TNF-a), 370 Cytomegalovirus (CMV), 394

Cytoplasmic membrane, antibiotics; see also Antibiotics polyether antibiotics, 431-432 polymyxin, 431 tyrothricin, 430-431 Cytotoxic T-lymphocytes (CTLs), 362

DCE, see Dynamic contrast-enhanced DCPG, see 3,4-Dicarboxyphenylglycine DDD, see Drug discovery and development Deactivation, definition, 210; see also Ion channels Dementia, cause, 263 Dendroaspis augusticeps, 273 Dendroaspis species, 270 5'-Deoxy-5-fluorocytidine (5'-DFCR), 382 5'-Deoxy-5-fluorouridine (5'-DFUR), 382 Deoxynucleotide triphosphates (dNTPs), 178 Deoxyxylulosephosphate-reductoisomerase, 351;

see also Malaria Depolarisation-induced suppression of excitation (DSE), 323 Depolarisation-induced suppression of inhibition (DSI), 323 Depression treatment, SSRI, 305; see also Transporter ligands Dereplication, definition, 97 Desipramine, 306 1,2-Diacylglycerol (DAG), 284 Diacylglycerol lipase, inhibitors, 327;

see also Cannabinoid receptors Diamine oxidase (DAO), 283 Diastereomers crystallization, 83 3,4-Dicarboxyphenylglycine, 81 Dichlorodiphenyltrichloroethane (DDT), 346 Differential crystallization, diastereomeric salts, 83 Dihydro-P-erythroidine (DH0E), 278 Dihydrofolate reductase (DHFR), 355, 368 Dihydropyridines, usage, 218

9-(1,3-Dihydroxy-2-propoxymethyl)guanine (DHPG), 410 Dimaprit, role, 288

Dimeric positive AMPA receptor modulators, design, 260-261

4,4-Diphenyl-3-butenyl (DPB), 242

Disease and ion channels, 211; see also Ion channels

Dissociation, enzyme inhibitor, 177

Distomer, side effects, 81

Diversity-oriented synthesis (DOS), 60-62

Dofetilide, 215 Dopamine (DA), 299-300 Dopamine transporter (DAT), 228, 233-236 Dorsal root ganglion, 221 Double-prodrug principle, 139

3D-pharmacophore model, ligand-based drug design, 45 initial pharmacophore model, 46-47 pharmacophore model extension, 48-50 principles to develop, 45

receptor essential volumes and exclusion spheres usage, 47-48

3D quantitative structure-activity relationships analysis (3D-QSAR analysis), 44 GRID molecular interaction fields, 53-55 substituted flavones development, 55-57 DRG, see Dorsal root ganglion Drug biodistribution study, 111-112 Drug design biostructure-based, 29-31 anti-influenza drugs, 31-33 experimental and computational methods, 41 fast-acting insulins, 37-41 HIV protease inhibitors, 34-37 chemical biology, 59-60 ligand-based

BZDs site of GABAa receptors, 44 3D-pharmacophore model, 45-50 3D-QSAR analysis, 53-57 pharmacophore modeling, 44-45 peptide and peptidomimetic drug design, 123-124 biological function-based design, 132-133 ligand-based design, 125-132 modeling and docking, 133 small molecules application, 63-65 generation, 60-63 stereochemistry, 79-83

determination, analytical methods, 87-88 pure stereoisomers preparation, 83-87 structure-based, 12 Drug development process, 5-6

Drug discovery and development; see also Drug design historical perspectives, 2-3 imaging, 107-108

limitation, 120-121 role, 119-120 multimodal imaging techniques, 108 conventional imaging, 109-110 molecular imaging approaches, 110-113 natural products antibiotics, 92-94 historical perspective, 91-92 as lead structures, 7-9 optimization, 99-105 screening, 94-99 in target identification, 6-7 optimization, 9-12 selected imaging applications biomarker, 117-119

lead optimization and drug profiling, 114-117

target validation, 113-114 Drug screening and ion channels, 211-212; see also Ion channels

Drug targeting, prodrug design, 146-147 D-sotalol, 215

DuPont Merck cyclic urea inhibitors, 37 Dynamic contrast-enhanced, 119

EAAT, see Excitatory amino acid transporters Electrical membrane potential, ion currents, 208-209;

see also Ion channels Electroencephalography (EEG), 330-331 Electromyelography (EMG), 330 Enantioselective chromatography, 84-85 Enfuvirtide, 404; see also Anti-HIV compounds env gene, 185

Enzymatic reactions, prodrug transformation, 137-138

Enzymes biostructure-based inhibitor design, 182 of HIV protease inhibitors, 185-188 of protein kinase inhibitors, 183-185 catalysis, 174-177 as drug targets, 173-174 inhibitor interaction modes, 174-175 mechanism-based inhibitor design intermediate state-based design, 179-182 substrate structure-based design, 178-179 usage, 73 Epipedobates tricolor, 277 EPL, see Expressed protein ligation Equilibrium potential, definition, 209;

see also Ion channels Erythropoietin (EPO) receptor, 71, 197 Escitalopram, discovery, 309-310 Essential metals, in medicine, 152 Ethylenediaminetetraacetic acid (EDTA), 158-159

Eudismic ratio (ER), definition, 79 Excitatory amino acid transporters, 250 Expressed protein ligation, 72 Extracellular loops (ECLs), 229 Extrapyramidal symptoms (EPS), 300, 303-304

FAAH-inhibitors and anandamide uptake inhibitors, 326;

see also Cannabinoid receptors Fast-acting insulins, 37-41; see also Biostructure-based drug design

Fatty acylethanolamide hydrolase (FAAH), 322 Fentanyl, 321

[18F]-2-fluoro-2-deoxyglucose (FDG), 118 Filariasis, 342-343; see also Neglected diseases FK506 binding protein (FKBP), 64 5-Fluoro-2'-deoxyuridine monophosphate (FdUMP), 381

Fluorometric Imaging Plate Reader (FLIPR™), 199, 212 [3-(4-Fluorophenyl)-3-(4'-phenylpheroxy)]

propylsarcosine, 238 5-Fluorouracil (5-FU), 381-382 5-Fluorouridine triphosphate (FUTP), 381 Folate synthesis, 355-356; see also Malaria Fragment-based approaches, drug screening, 62-63 Fusobacterium nucleatum, 228

GABAa and GABA ligands, structures, 245

GABA-aminotransferase, 241

GABAA receptor agonists, 336-337; see also

Slow wave activity (SWA) GABA-AT, see GABA-aminotransferase GABAB receptor, structure, 248 Gabapentin, 220 gag gene, 185 Galanthus nivalis, 269 Gating, definition, 210; see also Ion channels Genome instability and DNA mutation, 379-380;

see also Cancer Gleevec, 388-390; see also Cancer Glucagon-like peptide-1 (GLP-1), 73 Glucantime, 169 Glucocorticoids, 366-368 Glutamate, chemical structure, 38 Glutamate, neurotransmitter and excitotoxin receptor classification and uptake mechanisms, 249-251

Glutamic acid and GABA neurotransmitter systems, 240-241

Glutathione-S-Transferases (GST), 166 Glycinamide ribonucleotide formyltransferase (GARFT), 383-384

Glycine and GABA transporters, inhibitors, 237-238 Glycine-B (GlyB), 238

Glycine coagonist site, 253; see also Ionotropic glutamate receptor (iGluR) ligands Glycine transporters (GlyT), 237-238 Gold, role in medicine, 168-169 G protein and ß-arrestin signaling pathway, 7TM

receptors, 194 G protein-coupled receptor kinases (GRKs), 194 G-protein-coupled receptors (GPCRs), 124, 190, 192-194,

271, 284, 291, 299, 314, 323 GRID, in molecular interaction fields calculation, 53-55

Guanidinyl-NTI (gNTI), 318

Haemophilus influenzae, 440 Haloperidol, 301

Hard and soft acids and bases, 155-156

HBV infections, treatment, 416

HCN, see Hyperpolarization-gated channels

Helicobacter pylori, 289

Helminthic parasites, infections filariasis, 342-343 schistosomiasis, 342 Hemozoin formation, 346-349; see also Malaria Herceptin, 390-391; see also Cancer Her-2/neu tyrosine kinase receptor, overexpression, 113 Herpes simplex virus (HSV), 394 Hexamer insulin, x-ray structure, 39 HHV-8, see Human herpesvirus 8 High affinity glutamate transporters (SLC1), 225 High mobility group (HMG) proteins, 165 High-performance liquid chromatography-mass spectrometry (HPLC/MS), 92 High-throughput screening, 62, 285 Histamine H1 receptor agonists, 284-285 antagonists, 285-287 molecular aspects, 284 therapeutic usage, 287 Histamine H2 receptor agonists, 287-288 antagonists, 288-289 molecular aspects, 287 therapeutic usage, 289 Histamine H3 receptor agonists, 291 antagonists, 291-294 molecular aspects, 290-291 therapeutic usage, 294 Histamine H4 receptor agonists, 294-295 antagonists, 295-296 molecular aspects, 294 therapeutic usage, 296 Histamine N-methyltransferase (HMT), 283 Histamine receptor, 283-284 Histidine-decarboxylase (HDC), 283 Histocompatibility molecule (MHC), 361 Histone acetyl transferases (HATs), 386 Histone deacetylase (HDAC) inhibitors, usage, 385-388 HIV-1 protease; see also Biostructure-based drug design 3D structure, 34 inhibitors, 35

HIV protease inhibitors, structure-based design, 185-188 HIV-1 PR, usage, 185-187

HIV reverse transcriptase, nucleoside and nucleotide inhibitors, 178-179 HSAB principle, see Hard and soft acids and bases HSV infections, treatment, 416 5-HT2A antagonists, 337-338; see also Slow wave activity (SWA) HTS, see High-throughput screening Human herpesvirus 8, 202

Human immunovirus (HIV) protease inhibitors, 34-37 Human melanocortin receptor 4 (hMC4R), 125 Human steroid 5a-reductase inhibitors, 179 Huperzia serrata, 269

Hydrogen bonding and electrostatic interactions, 21-24;

see also Ligand-protein binding, molecular recognition

Hydrophobic effect, 24-25; see also Ligand-protein binding, molecular recognition

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA), inhibitors, 179-181 Hyperpolarization-gated channels, 212

IAA and GABA receptor, 248-249; see also y-Aminobutyric acid (GABA) iGluRs, see Ionotropic glutamate receptors Imatinib, usage, 183

Imidazole compound and H3 receptor, 292;

see also Histamine H3 receptor Imipramine, 305-306 Immune modulating agents, prospects, 373 Immune system antibodies, 363 cells, 360 B cells, 361 T cells, 361-363 diseases autoimmune disease, 364-365 cancer immunology, 365 inflammation, 365 NK cells, 363-364 role, 359-360 Immunomodulating biologics B cell depletion, 372-373 cytokines, 369-372 monoclonal antibodies, 369 recombinant protein and engineered proteins,

368-369 targeting T cells, 373 Immunosuppressive agents, 366-368 Induced fit theory, 15

Influenza virus neuraminidase, 3D structure, 32 Inhibitor design, mechanism-based, 177 Inhibitor interaction modes, enzymes, 174-175 Insomnia treatment, hypnotic drug, 329 Insulin, biosynthesis and function, 38-41 Insulin-dependent diabetes mellitus (IDDM), 364 Insulin secretion, mechanism, 213;

see also Ion channels Interferons (IFN), role, 369-370; see also Cytokines Interferon-stimulated response element (ISRE), 296 Interleukins (IL), role, 370-372; see also Cytokines International Nonproprietary Name (INN), 306 Intramuscular depot injections, prodrugs, 146 Ion channels, 207-208 cell membrane, 208 disease, 211

drug screening, 211-212 electrical membrane potential, 208-209 gating of, 209-210 ligand-gated, 223 molecular structures of, 211 opening, closing and inactivation, 210 physiological and pharmacological modulation, 211 physiology and pharmacology of voltage-gated, 213-214

structure of voltage-gated, 212-213 types, 210

Ion, intra and extracellular concentration, 208 Ionotropic GABA receptors, 243-246; see also y-Aminobutyric acid (GABA) Ionotropic glutamate receptor family, 196-197 Ionotropic glutamate receptor (iGluR) ligands AMPA receptor agonists, 253-254 AMPA receptors, modulatory agents, 255-256

competitive and noncompetitive AMPA

receptor agonists, 254-255 glycine coagonist site, 253 NMDA receptor antagonists, 251-252 NMDA receptor ligands, 250-251 uncompetitive/noncompetitive NMDA receptor antagonists, 252-253 Ionotropic glutamate receptors, 37 Iproniazid, 305

Iron, role in medicine, 162-163 Isoclozapine, 301-302 Isothermal titration calorimetry (ITC), 35 3-Isoxazolol amino acid, 11

Kainic acid (KA) receptor, 250 Kaletra, usage, 187-188 Kanamycin, 436

KA receptor, 256-257; see also Ionotropic glutamate receptors (iGluRs) K+ current, cardiac action potential, 209 Kir6 channels, expression, 213

Laburnum anagyroides, 278 P-Lactam antibiotics, 420-421; see also Antibiotics cephalosporins, 423-427 nontraditional, 427-429 penicillins, 421-423 Lamivudine, 404 Leflunomide, 366

Leishmaniasis, 343-345; see also Neglected diseases L-Glutamic acid decarboxylase (GAD), 241 Ligand and receptor, conformational changes, 19-21;

see also Ligand-protein binding, molecular recognition Ligand-based drug design

BZDs site of GABAa receptors, 44 3D-pharmacophore model, 45

initial pharmacophore model, 46-47 pharmacophore model extension, 48-50 receptor essential volumes and exclusion spheres usage, 47-48 3D-QSAR analysis, medicinal chemistry GRID molecular interaction fields, 53-55 for substituted flavones, 55-57 pharmacophore modeling, 44-45 Ligand-gated ion channels, 195-197, 223; see also

Ion channels Ligand-protein binding, molecular recognition, 15 affinity determination, 16-18

AGconf, 19-21

A^hydrophob, 24-25

AGvdw, 25-26 Ligand-protein complex, x-ray structure, 16 Lithium salts, role in medicine, 160 LNA, see Locked nucleic acid Loa loa, 342 Lobelia inflata, 278 Local conformational constraints, 127 Lock-and-key hypothesis, 78 Locked nucleic acid, 65 Loxapine, 301

L-Valine ester of ganciclovir (VGCV), 411 Lymnaea stagnalis, 195

mAChRs, see Muscarinic acetylcholine receptors Macromolecular prodrug, 146 Magnetic resonance imaging (MRI), 108 Malaria, 345-346 drugs

Ca2+ pump of plasmodium parasites, 349-351

deoxyxylulosephosphate-reductoisomerase, 351

folate synthesis, 355-356 hemozoin formation, 346-349 mitochondrial functions, 351-353 nonestablished targets, 353-355 resistance antifolate resistance, 357 chloroquine resistance, 357 4-quinolinemethanol resistance, 357 Malignant cancer, 375-378 Mannopeptimycin antibiotics, structure-activity relationships, 104 MAO-inhibitor and antidepressant drugs, 305; see also

Transporter ligands Mass spectroscopy methods, chiral drug analysis, 88 Matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS), 111 MDMA, see 3,4-Methylenedioxymetamphetamine Mechanism-based enzyme inhibitor design intermediate state-based design, 179-182 substrate structure-based design, 178-179 Medicinal chemistry, definitions, 1-2 Mefloquine, 354-355; see also Malaria Melanocortin receptors, 131 a-Melanocyte stimulating hormone (a-MSH), 131 Melatonin and melatonergic agonists, 338-339; see also

Sleep system, pharmacological modulation Melitracen, 306 Memantine, 241, 252

Membrane proteins, 37; see also Biostructure-based drug design Meperidine, 321

Metabotropic glutamate receptor ligands allosteric modulators, 259-260

A^transl+rot, 18 19

competitive metabotropic glutamate receptor antagonists, 258-259 metabotropic glutamate receptor agonists, 257-258 Metabotropic glutamate receptors (mGluRs), 115 Metal ions, categories, 155-156 Metastatic cancer, characteristics, 375, 378 Methadone, 321 Methicillin, 422 Methotrexate, 366, 368 3,4-Methylenedioxymetamphetamine, 236 mGluRs, see Metabotropic glutamate receptors Mibefradil, 220

MIC, see Minimal inhibitory concentration Microbial diseases treatment, antibiotics, 93 Micromonospora inyoensis, 437 Micromonospora purpurea, 436 Minimum inhibitory concentration (MIC), 103, 444 Molecular approach, target discovery, 4-5 Molecular imaging approaches, 110-113 Molecular interaction fields calculation, GRID, 53-55 Molecular recognition, ligand-protein binding, 15 affinity determination, 16-18 AG partitioning AGconf, 19-21

AGhydrophob, 24-25

AGp0lar, 21-24

AGtransl+rot, 18-19

AGvdw, 25-26 Molecular recognition, stereospecificity, 78-79 Monensin, 431-432

Monoacylglycerol lipase, inhibitors, 327; see also

Cannabinoid receptors Monoclonal antibodies, 369 Morphine, 313

chemical structure, 314 in receptor characterization, 6 usage, 91

Multimodal imaging techniques, 108 conventional imaging, 109-110 molecular imaging approaches, 110-113 Multiple sclerosis (MS), 364-365 Arecoline, conversion, 10

Muscarinic acetylcholine receptors (mAChRs), 271-272 allosteric modulators, 274 ligand binding, 274-275 mAChR agonists, 272-273 mAChR antagonists, 273-274 Muscimol, usage, 8-9 Mycobacterium tuberculosis, 99, 433

N-acetylglucosamine (NAG), 441-442 N-acetylmuramic acid (NAM), 441-442 nAChRs, see Nicotine acetylcholine receptors Na+/Cl-, binding sites, 231; see also Sodium-coupled neurotransmitter transporters (SLC6) Na+/Cl-coupled neurotransmitter transporter, structure, 230 Na+ current, cardiac action potential, 209 Naloxone, 321

Naltrexone, 321

Naltrindole (NTI), 318

Naphtoquinones, 352-353; see also Malaria

Native chemical ligation, 71

Natural killer cells (NK cells), 363-364; see also

Immune system Natural products, drug discovery, 89-90 antibiotics, 92-94 historical perspective, 91-92 optimization, 99-105 screening, 94-99 Nav channels, toxin-binding sites, 222 NCL, see Native chemical ligation Negative allosteric modulators, 203 Neglected diseases, 341-342

helminthic parasites, infections filariasis, 342-343 schistosomiasis, 342 malaria drugs, 345-346

Ca2+ pump of plasmodium parasites, 349-351

deoxyxylulosephosphate-reductoisomerase, 351 folate synthesis, 355-356 hemozoin formation, 346-349 mitochondrial functions, 351-353 nonestablished targets, 353-355 malaria resistance antifolate resistance, 357 chloroquine resistance, 357 4-quinolinemethanol resistance, 357 protozoan parasites, infection leishmaniasis, 343-345 trypanosomiasis, 343 Neomycin, 436 Neurotransmitters, role, 299 Neurotransmitter transporters, 225-227 SLC6 family, 227-228

structure and mechanism, 228-231 substrate binding and translocation, 231 substrate specificity and binding sites, 232-233

NFPS, see [3-(4-Fluorophenyl)-3-(4'-phenylpheroxy)]

propylsarcosine Nicotine acetylcholine receptors (nAChRs), 8, 68, 195, 276 allosteric modulators, 279-280 ligand binding, 280-281 nAChR agonists, 277-278 nAChR antagonists, 278-279 NMDA receptor antagonists, 251-252; see also Ionotropic glutamate receptor ligands (iGluRs) N-methyl-D-aspartate (NMDA), 115, 250 receptor antagonists, uncompetitive and noncompetitive, 252-253 (see also Ionotropic glutamate receptor (iGluR) ligands) receptor ligands, 250-251 (see also Ionotropic glutamate receptor (iGluR) ligands) N-methylscopolamine (NMS), 273 Nocardia mediterranei, 99 Nocardia mediterranii, 433 Noncompetitive inhibitors, 174

Nonenzymatic catalyzed bioco

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