Index

Note: Page Numbers followed by f indicate figures; t, tables; b, boxes.

A Affinity, definition, 134 Analgesics morphine, 55

α1-Adrenoceptor, 231 Affinity labeling agents, 240–246 Anaplastic lymphoma kinase, 339
Abacavir sulfate, 387 aspirin, 243–246 Anchimeric assistance, 170, 296–299
Abelson (Abl) kinase, 213–214 cephalosporins, 241–243 Andrews analysis, 56
Absorption, definition, 13 cephamycins, 241–243 Angiotensin converting enzyme (ACE), 68, 225
Absorption/distribution/metabolism and definition, 240 Angiotensin-converting enzyme inhibitors
excretion (ADME), 13 mechanism of action, 240–241 lead discovery, 226
ABT-199, 48 penicillins, 241–243 lead modification, 226–230
Abzyme, 432 Agonist, 132 mechanism, 226–230
ACE. See Angiotensin-converting enzyme dose response curve, 132, 134f–135f Angiotensin I, 225
(ACE) full agonist, 132 Angiotensin II, 225
Acetaminophen, 245–246, 383, 398, 447 inverse agonist, 132 Angiotensin III, 225
Acetylcholinesterase, 9, 52, 448–450 partial agonist, 132, 152 Angiotensin IV, 225
N-Acetylgalactosamine-6-sulfatase, 198 partial inverse agonist, 132, 152 Angiotensinogen, 225
Acromegaly, definition, 21 Agonists, function, 8–9 Anidulafungin, 26t
Activation-aggregation theory, 138 AIDS, 235 Antagonist, 132
Active analog approach, 40 Alanine racemase, 178–180 competitive antagonist, 132
Active site, 166 inhibitors as antibacterials, 208 dose response curve, 133f
Active-site directed irreversible inhibitor, Albendazole, 385–386 function, 8–9
238–239 Albuterol, 143, 397 non-competitive antagonist, 132
Activity, definition, 24 Alcohol dehydrogenase, 367, 387 Antedrugs, 405–407
Activity cliff, 57–58 Aldehyde dehydrogenase, 367, 387, 488 Anthracyline, 344
Activity landscape concept, 57–58 Aldehyde oxidase, 389 resistance to, 344
Acyclovir, 455 Aldo-keto reductases, 388 Anthracycline antitumor antibiotics, 307–308
Acyl CoA synthetases, 398–399 Aldosterone, 225, 230 Antiapoptotic proteins, 48
Acyl-coenzyme A cholesterol acyltransferase O6-Alkylguanine- DNA alkyltransferase, Antibodies, function, 124
(ACAT), 10 302–303, 344–346 Antibody-directed abzyme prodrug therapy
N-Acyltransferase, 399 Allopurinol, 247 (ADAPT), 431–432
ADAPT. See Antibody-directed abzyme Allosteric binding site, 211 Antibody-directed enzyme prodrug therapy
prodrug therapy (ADAPT) definition, 132 (ADEPT), 431
Additive, 76 Alprazolam, 446 Antibody-drug conjugate (ADC), 438
Adefovir, 430–431 Aminacrine, 292–293 Antibody-targeted chemotherapy, 438
Adefovir dipivoxil, 426, 430–431 Amine N-methyltransferases, 381 Antihistamines, definition, 139
Adenosine aminohydrolase, 221 l-Amino acid decarboxylase, 180 Antimetabolites, 210, 218, 256–257
Adenosine deaminase, 221, 348, 453 γ-Aminobutyric acid (GABA), 208 definition, 210, 218
Adenosine triphosphate (ATP), 22, 175, 5-Aminoimidazole-4-carboxamide-5′- Antineoplastic agents, 256–257
195–196 ribonucleotide transformylase, 186 definition, 256–257
S-Adenosylmethionine, 188 Aminopeptidase A, 225 Antipurines, 348
S-Adenosylmethionine decarboxylase, 251–252 Aminopeptidase N, 225 AP endonucleases, 276
ADEPT. See Antibody-directed enzyme Aminotransferases, 180–184 Apoptosis, 48, 223, 276
prodrug therapy (ADEPT) Amitriptyline, 151, 373 definition, 223
ADME, definition, 13 Amlodipine, 377 Approximation, 169–170, 174–175
ADME descriptors, computational methods, 89 Amoxicillin, 247, 443 Apramycin, 347
ADME-tox assessments synergism with, 347 APS phosphokinase, 397
Caco-2, 44 Amoxicillin (Amoxil), 241 Arene oxides, 368
cytochrome P450 enzymes, 44 AmpC β-lactamase, 46 Aromatase, 367
hERG, 44 Amphetamine, 61 Aromatic l-amino acid decarboxylase,
α-Adrenergic receptor, 144–145 Ampicillin, 241, 439–440, 443 254–255, 457–458
β2-Adrenergic receptor, 42, 143 synergism with, 347 Arylhydroxamic acid N,O-acyltransferase, 382
β-Adrenergic receptor, 142 Amsacrine, 292–293 Ascorbic acid, 175
β2-Adrenoceptor, 232 resistance to, 339 Asparaginase, 198
Adriamycin, resistance to, 346 Amylase, 198 l-Asparagine amidohydrolase, 198

507
508 Index

Aspartate aminotransferase, in a problem, 200 Bioreductive alkylation, 303–305 Cetylpyridinium chloride, 406
Aspartate transcarbamylase, 223, 344 Bipartite prodrug, 424 Chain branching, 61–62
synergism with, 349–350 Bis-intercalating agents, 295 Charge relay system, 172
Aspirin, 243–246, 392, 434–435 Bleomycin, 308–310 Charge-transfer complexes, 128–129
mechanism of action, 243–244 resistance to, 343 Cheese effect, 254
Atom pair method, 39 Bleomycin hydrolase, resistance to, 343 Chemotherapeutic agent, definition, 126
Atorvastatin, 89f, 405 Blockbuster drug, definition, 155 Chemotherapy, definition, 208
ATP binding cassette, 346 Blood brain barrier, 74, 249, 430 Chiral switch, 143
ATP sulfurylase-catalyzed reaction, 397 log p, 75–76 Chlorambucil, 59, 297–299, 403
Atrial natriuretic peptide (ANP), 230 properties to cross, 81–82 Chloramphenicol, 395
Atropine, 124 BOMB, 42–43 Chlorcyclizine, 139
Atropisomers, 149–151 Bortezomib, resistance to, 340 Chlordiazepoxide HCl, 4
AutoDock, 41 Bradykinin, 225 Chloroquine, 129
Auxophore, definition, 55 Brentuximab vedotin, 438 Chlorothalonil, 129
Azapeptides, 70–71 Brivanib, 425–426 Chlorothiazide, 57
Azathioprine, 400 Brompheniramine, 399 Chlorpromazine, 67, 151, 370
Azatides, 70–71 Bryostatin 1, 91–92 Chlorprothixene, 145
Azoreductases, 390 Bupivacaine, 141 Cholesterol biosynthesis, 232–233
Buprenorphine, 56 Chromatin, 281
Bupropion hydrochloride, 6 Chromoprotein enediyne antibiotics,
B
Busulfan, 299, 400 311–312
Bacampicillin, 439–440
Butaclamol, 141–142 α-Chymotrypsin, 172
Baclofen, 141
Butamben, 129 Cilastatin, 402
Bacterial cell wall biosynthesis inhibitors, 24
Butanilicaine, 392 Cimetidine, 444
Bacteriodal vs. bacteriostatic, 217, 241–242
Bystander killing effect, 431 case history, 151–156
Bacteriostatic vs. bacteriocidal, 217, 241–242
Cladrabine, resistance to, 344
Base tautomerization, 279–280
Clavulanate, synergism with, 347
Bcl-2, 276 C
Clavulanic acid, 247
Bcr-Abl, 337–338 Cabozantinib, 349
Cleavable complexes, 284, 291
active conformation, 215 Caco-2, 44
α-Cleavage, 186
imatinib target, 213–214 Calcitonin gene-related peptide receptor, 66
Click chemistry, 52
inactive conformation, 215 Calicheamicin, 313–314, 438
Clindamycin, 435
Benserazide, 457 Cannabinoid receptors CB1 and CB2, 245
Clindamycin palmitate, 435
Benzocaine, 429 Captopril, 68, 404–405
Clindamycin phosphate, 435
Bergman rearrangement, 314 as slow, tight-binding inhibitor, 225–228
Clinical drug, 1
Beta-blockers, 142, 228 Carbamazepine, 373, 451
definition, 1
definition, 142 Carbidopa, 255, 457–458
Clinical trials, different phases, 14
Bifunctional alkylating agents, 297 Carbonic anhydrase, 165, 444
Clomethiazole, 404
Bifunctional intercalating agents, 295 Carboxypeptidase, 431–432
Clonazepam, 389, 402
Bilirubin oxidase, 198 Carboxypeptidase, D-alanine-D-alanine
Clopidogrel, 239, 450–451
Binding energy carboxypeptidase, 174–175
Clorgyline, 255–256
of functional group, 131 Carboxypeptidase A, 226–227
Cloxacillin (Cloxapen), 241
loss of entropy, 131 Carboxypeptidase G2, 431–432
Cluster analysis, 87–88
Binding specificity, 167 Carmustine, 301
Clustering, definition, 36
Bioactive conformation, 41, 66 Carrier-linked prodrugs, 424–443
Clusters, 43–44
definition, 146 examples of, 428–435
Cocaine, 2, 392
Bioassay, definition, 24 for improved absorption and distribution, 429
Codeine, 2, 55, 385, 404
Biochemical and Organic Model Builder for increased water solubility, 428–429
Codrug, 424
(BOMB), 42 properties of, 425–427
Coenzyme, 166
Bioinformatics, 93–95 for site specificity, 429–433
catalysis, 175–196
Bioisosteres types of, 425–428
definition, 175
definition, 62 Caspases, 170
Coenzyme A, 175, 177, 195–196
effects of, 62 Catalase, 168
thioesters role, 196
nonclassical bioisosteres, 62 Catalyst, 40
Cofactor, 166
Bioisosterism, 62–66 Catalytic triad, 172, 174–175
definition, 175
Bioprecursor prodrugs, 443–458 Catecholamine O-methyltransferase, 254
Colchicine, 2
decarboxylation activation, 457–458 Cathepsin B, 240
Collagenase, 198
elimination activation, 445–446 Cation-π interaction, 130
Collected products hypothesis, 226–227
hydrolytic activation, 445 (+)-CC-1065, 300–301
Combination chemotherapy, 276–277
nucleotide activation, 454–455 C-C chemokine receptor type 5 (CCR5), 151
Combinatorial chemistry, 27
omeprazole, 444–445 Celecoxib, 245, 405
Compactin, 232
oxidative activation, 446–452 Cellulase, 198
Comparative binding energy analysis
phosphorylation activation, 455–457 Cephalosporins, 241–243
(COMBINE), 39–40
proton activation, 444–445 Cephamycins, 241–243
Comparative molecular field analysis (CoMFA),
reductive activation, 452–454 Cereblon, 140
39–40
sulfation activation, 457 Cerivastatin, 234
Index 509

Comparative molecular moment analysis Dead-end complex, 455 reversible DNA binders, 288–295
(CoMMA), 40 4’-Deaza-1’-aza-2’-deoxy-1’-(9-methylene) toxicity of, 276
Comparative molecular similarity indices immucillin-H, 222-223 DNA ligases, 276
analysis (CoMSIA), 39–40 Decarboxylases, 180 DNA nucleotidyl transferase, 302
Competitive reversible inhibitor L-amino acid decarboxylase, 180 DNA polymerases, 276
definition, 210 Dehydrogenases, 190 α-DNA polymerases, 455
examples, 211, 238 Dehydropeptidase I, 402 DNA protein kinases, 276
Composition of matter patent, 23 Delavirdine, 23 DNA repair enzymes, 276
Computational methods, 83–93 Deoxyribonuclease, 198 DNA shapes, 280–286
Conformational change, 166, 168, 173–175 Designer drug, 255 DNA strand breakers, 307–317
Conformational constraints, 66–68 Desolvation, 173 anthracycline antitumor antibiotics, 307–308
analogs, 66–67 Dexlansoprazole, 444 bleomycin, 308–310
Conformationally rigid analogs, 66, 147 Dexchlorpheniramine, 140 enediyne antitumor antibiotics, 311–317
Congeneric series, 85 Dextropropoxyphene, 55–56, 141 sequence specificity for, 317
Conjugate compounds, pKa and activity, 80 Diazepam, 5, 382 tirapazamine, 310–311
Constitutive, 76 Diazoxide, 57 DNA structure, 277–287
Cotinine, 379–380 Dibucaine, 131 base tautomerization, 279–280
Covalent bonds, 126 Diclofenac, 370 chromatin, 280–281
Covalent catalysis, 170, 174–175 Diethylstilbestrol, 78 DNA conformations, 286–287
COX-1 and COX-2, 244–245 α-Difluoromethylornithine, 247 DNA shapes, 280–286
inhibition of, by NSAIDs, 244–245 eflornithine, 251–252 duplex DNA, 281
COX-2 selective inhibitors, 245 α-Difluoromethylputrescine, 252–253 histones, 280–281
celecoxib, 245 Digitoxin, 3 nucleosomes, 280–281
rofecoxib, 245 Digoxin, 3 pitch, 286
valdecoxib, 245 Dihydrofolate reductase, 184–186, 257, properties, 277–287
COX-3, 245–246 277, 437 DNA topoisomerase, 281–282, 291
Craig plots, 86–87 resistance to, 334, 340 classification, 283
Crizotinib, resistance to, 339 synergism with, 348 mechanisms, 284–286
Cross validation, PLS with, 88 in thymidylate synthase mechanism, 257 DOCK, 41–42
Cruzain, 42 Dihydroorotate dehydrogenase, 446 Docking, definition, 41
Cyclin-dependent kinase (CDK2), 51–52 Dihydropteroate synthase, 218–219, 334 Donepezil hydrochloride, 87–88, 450
Cyclooxygenase (COX), 243–244, 384 inhibition by sulfanilamide, 218 l-Dopa, 457
Cyclophosphamide, 447–448 synergism with, 348 Dopa decarboxylase, 180, 457
Cyproheptadine, 380 Dimenhydrinate, 6 Dopamine, 11
Cysteine conjugate N-acetyltransferase, 400 Dipeptidyl peptidase-4, in diabetes, 234 Dopamine-D2 receptor, 148. See also
Cysteinylglycine dipeptidase, 400 Diphenhydramine, 78, 399 D2-dopaminergic receptor.
Cytarabine, 438, 443 Dipivaloylepinephrine, 429, 434 Dopamine receptor, 7f, 12
Cytidine kinase, 344 Dipole-dipole interactions, 126 Dose-response curve, 131
Cytochrome b5, 190 Directed evolution, 197–198 Double prodrug, 438–439
Cytochrome P450, 167, 192–194, 247, 365–391 DISCO, 40 Doxorubicin, 294–295, 307, 432
3A4, 350 Disease causes, 20–21 synergism with, 350
enzymes, 44 Distance geometry approach, 39 Dragon, 88
molecular properties, 366 Distomer, 140 D2-receptor, 232. See also D2-dopaminergic
in a problem, 201 Distribution, definition, 13 receptor.
synergism with, 348 Diversity-oriented synthesis, definition, 27 Drop-based microfluidics, definition, 24
DNA alkylators, 295–307 Drug, definition, 1
anchimeric assistance, 296 Drug administration
D
(+)-CC-1065, 300–301 intramuscular injection, 358
Dabigatran, 427–428
duocarmycins, 300–301 intravenous (IV) injection, 358
Dabigatran etexilate, 427–428
ethylenimines, 299 pulmonary absorption, 358
Dabrafenib, synergism with, 349
methanesulfonates, 299 rectal route, 357–358
Dacarbazine, 303
nitrogen mustards, 295–299 subcutaneous injection, 358
Dactinomycin, 293–294
DNA alkylators, metabolically activated sublingual route, 357–358
resistance to, 346
alkylating agents, 301–307 topical application, 357–358
DADMe-ImmH, 222–223
DNA footprinting, 308 Drug candidate, definition, 1
D-Amino acids, 190
DNA glycosylases, 302, 276 Drug chirality, 140–145
Dapsone, 400–402
DNA gyrase, 283 Drug development, 13–14
Dasatinib, 337–338
DNA-interactive drugs, 287–317 Drug discovery, 2–7
resistance to, 346
basis for, 275–276 librium, 4–5
Daunomycin
combination chemotherapy, 276–277 of penicillins, 3–4
with nucleic acid target, 7–8
DNA alkylators, 295–307 through clinical observations, 6–7
resistance to, 346
DNA strand breakers, 307–317 through metabolism studies, 5–6
Daunorubicin, 294–295, 307, 443
drug interactions, 277 without rational design, 2–7
D1-dopaminergic receptor, 141
drug resistance, 277 Drug–drug interactions, 366
D2-dopaminergic receptor, 141, 148, 232
external electrostatic binding, 289 definition, 12
Deacetylases, 393
510 Index

Drug latentiation, 424 Dunathan hypothesis, 178 importance, 208–210

Drug-like molecules, 33 Duocarmycins, 300–301 specificity, 210
Drug-like properties, 32, 36, 74 Duplex DNA, 281 target enzymes for drug design, 208
Drug metabolism, 211 Dynemicin A, 314 Enzyme prodrug therapies, 431
definition, 357 Enzymes, 165–168
stereoselectivity, 364–365 E characteristics of, 165
Drug metabolites EC50, definition, 131 function, 9
analytical methods in, 361–363 ED50, 59, 84 properties of, 165
computational prediction, 365 definition, 131 Enzyme saturation, irreversible inhibitor, 240
identification, 362–363 Effective molarity, definition, 169–170 Enzyme-substrate complex, 166–167
quantification, 363 Efficacy, definition, 134 Ephedrine, 2
sample preparation, 361 Efflux pumps, 346 Epidermal growth factor (EGF), 211–212
separation, 361–362 ATP binding cassette, 346 inhibitors, 212
Drug-receptor interactions, 125–157 breast cancer resistance protein, 346 Epidermal growth factor receptor (EGFR)
conformational isomers, 146–149 p-glycoprotein, 346 kinase, 211–213, 339
determination of, 131–134 Eflornithine, 247 inhibitors, 212
diastereomers, 145–146 EGFR kinase, 344 Epinephrine, 429, 434
forces involved, 125–131 E·I complex, 210–211, 240 Epoxide hydrolase, 371, 400
theories for, 134–139 Elastase, 170 Ergotamine, 357–358
Drug resistance, 333–346 Electronic effects, 72–73 Erlotinib, 212–213, 344
acquired resistance, 333 Electrostatic catalysis, 172–175 with cabozantinib, 349
activation of new pathways, 344 β-Elimination, 184 resistance to, 339
adriamycin, 346 Elog Doct, 78 synergism with, 349
altered drug distribution to the site of action, Elog Poct, 78 with tivantinib, 349
346 Enalapril Erythromycin, 359, 435
altered target, 334–340 as prodrug, 229 ethylsuccinate, 435
aminoglycoside antibiotic resistance, as slow, tight-binding inhibitor, 225–232 E-S complex, 166–168, 174–175
346 Enalaprilat, 229 Esomeprazole, 143, 239, 444
dactinomycin, 346 Endogenous ligand, definition, 20 Esperamicins, 313
daunomycin, 346 Endothelin-converting enzyme (ECE), 17α-Ethynyl estradiol, 21
decreased activating mechanism, 344 230–231 Etofenamate, 403
definition, 333 Enediyne antitumor antibiotics, 311–317 Etomidate, 393
development of dasatinib, 337–338 calicheamicins, 313–314 Etoposide, 292, 429
endogenous resistance, 334 esperamicins, 313–314 Etorphine, 56
exogenous resistance, 334 Enoyl reductase, 223–225 E-Triprolidine, 145
increased drug-destroying mechanisms, Enzymatic synthesis, 196–198 Eudismic ratio, 140
341–344 Enzyme-catalyzed reactions Eutomer, 140
intrinsic resistance, 333 adenosine triphosphate, 195–196 EVA, 40
mechanisms, 334–346 anchimeric assistance, 170 Excretion, definition, 13
overproduction of the substrate/ligand for the approximation, 169–170 Extended-connectivity fingerprints, 38
target protein, 341 binding specificity, 167 External electrostatic binding, 289
overproduction of the target, 340–341 coenzyme A, 195–196 Extrathermodynamic method, 85
penicillins, 346 coenzyme catalysis, 175–196 Ezetimibe, 10
primary resistance, 333 conformational change, 183–184
reversal of drug action, 344–346 covalent catalysis, 170 F
secondary resistance, 333 desolvation, 173 False negatives, definition, 36
sulfa drugs, 346 effect of pKa on, 171–172 False positives, definition, 34
Drug synergism, 346–352 electrostatic catalysis, 172–173 Famciclovir, 456
efflux pump inhibitors, 350 general acid-base catalysis, 170–172 Famotidine, 155
inhibition of a drug-destroying enzyme, heme dependent enzymes, 192–195 Fenclofenac, 370
346–348 mechanisms of, 169–175 Fenfluramine, 377
inhibition of targets in different pathways, nicotinamide adenine dinucleotide, 184 Fenoterol, 395
349–350 nonproductive binding, 167 Fenton reaction, 308
mechanisms of, 346–352 prochiral, 184–186 Ferguson’s principle, 83–84
sequential blocking, 348–349 pyridoxal 5′-phosphate, 178–184 Fexofenadine, 5, 358
use of multiple drugs for the same target, rate acceleration, 168 Fibonacci search method, 86–87
350–352 reaction specificity, 168 Fibrinolysin, 198
Drug targets, 7–10 specificity of, 167–168 Finasteride, 231
Dual-acting drugs, 230–232 strain/distortion, 173–174 Fingerprint, 38
Dual-acting enzyme inhibitors, 230–232 transfer of one carbon units, 184 First-pass effect, 357, 433
advantage, 230 Enzyme inactivator, 210 Flavin, 189–192
definition, 230 definition, 208, 238–239 Flavin adenine dinucleotide (FAD),
dual enzyme-activated inhibitor, 458 Enzyme inhibitors 186, 189
example of, 230 definition, 208 Flavin dependent enzymes, 189
Duloxetine, 23 ideal inhibitor properties, 210, 219 mechanisms, 190
Index 511

Flavin hydroperoxide, 190, 192 Gefitinib, 22, 212–213, 344 High-throughput screens, definition, 11
Flavin monooxygenases, 192, 366–367 resistance to, 339–340 Histamine H, receptor, 139
stereoselectivity, 366–367 Gemcitabine-HCI, 247 Histamine H2 receptor, 151–152
Flavin mononucleotide, 189 Gemtuzumab ozogamicin, 438 Histamine H4 receptor, 23
Flavoenzymes. See Flavin dependent Gene-directed enzyme prodrug therapy Histones, 280–281
enzymes (GDEPT), 432–433 Hit confirmation, 43
Flavoprotein monooxygenase, 380 Gene knockout, 9–10 Hit-directed nearest neighbor screening
Flex-S, 40 General acid-base catalysis, 170–172, 174–175 definition, 36
Flex X, 41 General acyl-CoA dehydrogenase, 190, 196 Hits, definition, 34, 43
Floxuridine, 256–258, 438 General catalysis, 170–171 Hit-to-lead process, 43–45
Fluconazole, 340 Genome HIV protease, 71
resistance to, 346 definition, 1 HIV-1 protease, 235, 335
Fludarabine, resistance to, 344 number of genes, 9–10 H+,K+-ATPase, 444
Fluid mosaic model, 74 Genomics, 93–95 HMG-CoA reductase, 9
Fluocinolone acetonide, 429 definition, 1 statin inhibition, 232–234
Fluocinonide, 429 Glide, 41 Hologram QSAR, 40
5-Fluoro-2’-deoxyuridylate, 256–258 Glucagon-like peptide-1 (GLP-1), 234 Homologation, 60–61
5-Fluorouracil, 256–258, 441–442, 454–455 Glucocorticoid receptor, 406 Homology model, 40–41
mechanism of action, 257–258 Glucose-dependent insulinotropic polypeptide, definition, 197–198
metabolism of, 257 234 Human immunodeficiency virus type 1
Fluoxetine, 143 β-Glucuronidases, 393 integrase (HIV-1 IN), 39
Fluphenazine, 434 Glucuronidation, 395 Hybrid drug, 142
Fluphenazine decanoate, 434 Glutamate decarboxylase, 10 definition, 142
Fluphenazine enanthate, 434 Glutamate receptors, N-methyl-D-aspartate Hydralazine hydrochloride, 247
Flutamide, 374–375 (NMDA) subclass, 148 Hydride displacement law, 62
Fluvastatin, 89f l-Glutamic acid, in epilepsy, 248–249 Hydrochlorothiazide, 228
fMF, definition, 33 l-Glutamic acid decarboxylase, in epilepsy, Hydrogen bonds, 32, 126–128
Focused library, 44 248–249 intermolecular, 127
Folic acid, 184 γ -Glutamyltranspeptidase, 400 intramolecular, 127–128
biosynthesis, 218 l-γ-Glutamyltranspeptidase, 458 Hydrophobic interactions, 129–130
Formyltetrahydrofolate, 186 Glutathione, 175, 400 3-Hydroxy-3-methylglutaryl coenzyme A, 232
Forodesine, 222–223 Glutathione S-transferase, 343–344, 371, 399–400 p-Hydroxyphenylacetate 3-hydroxylase, in a
Fosfomycin, 336f (+)-Glutethimide, 374 problem, 201
Fostamatinib, 427 Glycoprotein IIb/IIIa, 68–69 5-Hydroxytryptamine 1A receptor, 141
Fotemustine, 302 GOLD, 41 Hyperforin, 366
Fractional cell kill hypothesis, 276 G protein-coupled receptors (GPCRs), Hypoxanthine-guanine
Fragment-based drug design (FBDD), 46 definition, 123–124 phosphoribosyltransferase, 344, 454–455
Fragment-based lead discovery, 45–54 GRID, 41, 90
attributes, 45 GRIND, 40 I
limitations, 45 Groove binding, 289–290 Ibuprofen, 167, 245, 365, 436
Fragment-based screening, definition, 11–12 Guanethidine, 380 IC50, 84
Fragment evolution, 51 Guanylate kinase, 455 conversion to Ki, 210
Fragment hopping, 43 definition, 132
Fragment linking, 51 H Idiopathic vs. symptomatic disease, definition,
Fragments Half-life, definition for inhibitor, 225 248–249
definition, 45 Haloalkane dehalogenase, in a problem, 200 Idiosyncratic drug toxicities, definition, 241
linking, 51 Halogen bonding, 130 Idiosyncratic toxicity, 60
properties, 45 Haloperidol, 434 Imatinib, 213–216
transforming into leads, 51 Haloperidol decanoate, 434 binding mode, 215–216
Fragment self-assembly, 51 Halothane, 387, 391 inhibition of other kinases, 216
Free and Wilson or de novo method, 88–89 Hammett equation, 72 lead discovery and modification,
Fsp3, definition, 33 Hammett’s postulate, 72–73 214–215
Functional group modification, 57 Hansch analysis, 84–85 resistance to, 337–338, 340, 346
Hansch equation, 84 Imipenem, 402
G Hard and soft drugs, 405–407 Imipramine, 151, 377–378
GABA. See γ-Aminobutyric acid (GABA) Heme, 175 ImmH, 222–223
GABA aminotransferase (GABA-AT), Heme dependent enzymes, 192–195 Immobilon, 140
208, 239 Henderson–Hasselbalch equation, 80 Immucillin-H, 222–223
in epilepsy, 248–249 hERG, 44 Incretins, 234
GABAB receptor, 141 hERG channel, 358 IND, 93
β-d-Galactosidase, 198 Heroin, 55 Indacrinone, 141
Ganciclovir, 456 H1 histamine receptor, 139 Indomethacin, 385, 453
Gatekeeper residue, 339 High-throughput organic synthesis (HTOS) Induced-fit hypothesis, 166, 173–174
GDEPT. See Gene-directed enzyme prodrug solid-phase library synthesis, 27–30 Induced-fit theory, 137
therapy (GDEPT) solution-phase library synthesis, 30–31 Influenza A (H1N1) virus, 25t
512 Index

InhA, 223–225 β-Lactamases, 247, 341–342 Lipophilicity substituent constant, definition, 76

Inosine 5′-monophosphate dehydrogenase, 350 synergism, 347 Lisdexamfetamine, 130
Insulin, 234 Lactase, 198 Lisinopril, as slow, tight-binding inhibitor, 225,
Intellectual property, 13 Lamivudine, resistance to, 334 229, 230f
Intercalators, 290–292 Lanosterol C14α- demethylase, resistance to, 340 Lock and key hypothesis, 166
amsacrine, 292–293 Lanreotide, 21 Log D, 76
bis-intercalating agents, 295 Lansoprazole, 239, 444 Log P, 32, 44, 75–76, 293
dactinomycin, 293–294 LD50, 59, 84 branching effects, 76
daunorubicin, 294–295 Lead compound, 1 computer automation of, 78–79
doxorubicin, 294–295 definition, 1 derivation, 75–76
Intermolecular hydrogen bonds, 127 Lead compounds polar surface area, 81–82
Intramolecular hydrogen bonds common sources of, 11 Log Po, 75–76, 84
effect on lipophilicity, 127–128 properties of, 11 Lomustine, 301
order of stability, 127 Lead discovery Lopinavir, 335
Intrinsic activity, definition, 134 endogenous ligand, 20–23 synergism with, 348
Intrinsic maximum response, definition, 134–137 high-throughput screening (HTS), 24 Lorentz–Lorenz equation, 84
Investigational new drug (IND), 93 other known ligands, 23 Losartan, 388
definition, 13 overview of, 11–12 Loteprednol etabonate, 406
In vivo toleration (IVT), 82–83 screening by electrospray ionization mass Lovastatin, 232–234
Ion channel, structure and function, 123–124 spectrometry, 37 inhibitor of HMG-CoA reductase, 232–234
Ion-dipole interactions, 126 screening by NMR, 37 lead modification, 234
Ionic (or electrostatic) interactions, 126 screening of compounds, 24–54 mechanism of action, 233–234
Ionizable compounds sources of lead compounds, 20–54 LUDI, 42
conjugate compounds, 79–80 Lead-like molecules, 33–34 Lumiracoxib, 405
effect of polarity on, 81 Lead-like properties, 33–34, 74 Lyophilization, definition, 30–31
pKa and activity, 80 Lead modification, 54–95
potency, lipophilicity, 79–81 computational methods, 83–93
M
Iproniazid, 253 overview of, 12–13
Macromolecular drug carrier systems, 435–438
Irreversible enzyme inhibitors, 210, 238–258 Lead optimization, 54
poly(α-amino acids), 436–437
definition, 210, 238 Lead properties, 20
synthetic polymers, 436
Isomeric ballast, 140 LEAPT. See Lectin-directed enzyme-activated
Macromolecular perturbation theory, 137–138
Isoniazid, 223–225, 400–402 prodrug therapy (LEAPT)
Magic methyl interaction, 129
Isoproterenol, 357–358, 404 Lecithin cholesterol acyltransferase, 403
Major groove, 288–295, 299
Isosteres Lectin-directed enzyme-activated prodrug
Mass fragmentography, 363
backbone, 70–71 therapy (LEAPT), 432
Mass spectrometry
classical, 62 Leflunomide, 445–446
APCI, 362
nonclassical, 62 LEGEND, 42
CE-MS, 362
Isozymes, 366 Leinamycin, 305–307, 445
CI, 362
Isradipine, 23 Levalbuterol, 143
EI, 362
Ixabepilone, 26t Levodopa, 457
ESI, 362
Levopropoxyphene, 141
FAB, 362
K Levorphanol, 55–56
GC-MS, 362
Kanamycins, resistance to, 342 Library, definition, 23
LC-MS, 362
KatG, 223–225 Librium, discovery of, 4–5
LC/MS/MS, 362
kcat, 168, 220 Lidocaine, 380
MALDI, 362
Kd, definition, 125, 131 Ligand, definition, 20
SIMS, 362
d-Ketamine, 140 Ligand-based pharmacophore model, 40
soft ionization, 362
Ketoprofen, 141 Ligand efficiency and log P (LELP), 44
Matrix metalloprotease, 46–48
Ki, 240 Ligand lipophilicity efficiency, 44
Mechanism-based enzyme inactivators,
definition, 210 Ligand scout, 40
247–258
kinact Ligase, 198
advantages, drug design relative to affinity
in affinity labeling, 240 Linaclotide, 21
labeling agents, 247–248
in mechanism-based enzyme inactivators, Linear free energy relationship, 72–73
clavulanate, 347
247 Linezolid, 360, 368–369
definition, 247
Kinase, 208 Linkage number, 281
eflornithine, 250–253
Kinetic isotope effect (KIE), 359–360 Lipase, 196–197
floxuridine, 256–258
in transition state determination, 220 Lipoic acid, 175
5-fluoro-2’-deoxyuridylate, 256–258
KIT, 216 Lipophilicity effects, 74–79
5-fluorouracil, 256–258
Km, 211 effect on promiscuity and toxicity, 82–83
rasagiline, 254–256
koff, 240 importance of, 74
selegiline, 254–256
log P determination, computer automation
sulbactam, 347
of, 78–79
L theoretical aspects, 247
measurement of, 74–78
Labetalol, 142 tranylcypromine, 253–254
membrane lipophilicity, 79
Lacosamide, 129–130 vigabatrin, 248–249
partition coefficient, 75
β-Lactam antibiotics, 241 Mechlorethamine, 297
Index 513

Medicinal chemistry, 1 MolDock, 41 NIH shift, 368

folklore, 2–3 Molecular activity map, 58–59 Nilotinib, 337–338
Medicines, definition, 1 Molecular graphics resistance to, 346
Melphalan, 297–299 bryostatin 1, 91–92 Niridazole, 389
Membrane, functions, 74 definition, 90 Nitrofurazone, 389
fluid mosaic model, 74 paclitaxel, 91 Nitrogen mustards, 295–299
Meperidine, 55–56, 255 thymidylate synthase, 91 chemistry, 296–297
6-Mercaptopurine, 454–455 zanamivir, 90 lead modification, 297–299
resistance to, 344 Molecular graphics, 90–93 resistance to, 343
Mesoridazine, 385–386 Molecular shape analysis, 39 Nitroglycerin, 357–358, 400
Metabolically activated alkylating agents, Monacolin K, 232 Nitro reductase, 389
301–307 Monoamine oxidase (MAO), 61, 192, 247, 253, Nitroreductase, 433
leinamycin, 305–307 367, 375 Nizatidine, 155
mitomycin C, 303–305 Monoamine oxidase A, 458 NOAEL, 60
nitrosoureas, 301–303 Monoamine oxidase B, 457 Nonproductive binding, 167
triazene antitumor drugs, 303 Morphine, 2, 55, 385, 400, 404 Norethindrone, 389, 437
Metabolically activated inactivator, 247 Morphine 6-dehydrogenase, 400 Norgestrel, 387, 389
Metabolic switching, 368–369 MPTP, 255–256 (+)-Norgestrel, 21
Metabolism, definition, 5, 13 Multidrug resistance, 340 Nortriptyline, 397
Metabolites, definition, 5, 13 pumps, 346 Nuclear receptors, function, 124
Methadone, 55–56 Multiple copy simultaneous search (MCSS), 41 Nucleophilic catalysis, 170
Methanesulfonates, 299 Multiple reaction monitoring, 363 Nucleosomes, 281
Methdilazine, 67 Multistate receptor model, 139
Methenamine, 435 Multisubstrate analogs, 220, 223–225
Methenyltetrahydrofolate, 186 Mu-opioid receptors, 55 O
Occupancy theory, 134–137
N5,N10-Methenyltetrahydrofolate Muscarinic receptor, 147
Omega oxidation, 374
cyclohydrolase, 186 Mutant, definition, 172–173
Omeprazole, 143, 444–445
Methimazole, 247 Mutual prodrug, 424
Oral bioavailability, 79–81
Methionine adenosyltransferase, 403–404 Mycophenolate mofetil
rule of 5, 32
Methitural, 385 prodrug, 350–351
Veber rules, 33
Method of use patent, 23 synergism with, 350–351
Orotate phosphoribosyltransferase, 257
Methotrexate, 437
Orexin
Methotrexate, synergism with, 348 N receptor 1, 156
Methoxamine, 385 NADH, 184 receptor 2, 156
Methylenetetrahydrofolate, 186, 257 NADPH, 184, 192–194 Ornithine decarboxylase, 251
in thymidylate synthase mechanism, 257 NADPH-cytochrome P450 reductase, 192–194, Orotidine 5′-monophosphate decarboxylase,
N5,N10-Methylenetetrahydrofolate 307, 310–311, 366 165, 167
dehydrogenase, 186 Nalidixic acid, 291 Oxacillin (Bactocill), 241
N5,N10-Methylenetetrahydrofolate reductase, Naltrexone, 389, 434 Oxazepam acetate, 393
186 Naproxen, 245 Oxidases, 190
Methylprednisolone, 428–429 Natural selection, 333 N-Oxidation, 376
Methylprednisolone sodium succinate, 429 Navitoclax, design, 48 flavin monooxygenases and cytochrome
Methyl salicylate, 127 Nebivolol, 143 P450, 376–377
Methyltetrahydrofolate, 186 Negative cooperativity, 290 Oxidative deamination, 375–377
Methyltransferases, 403–404 Negative efficacy, 134–137 Oxidative N-dealkylation, 376
Metiamide, 154 Neighbor exclusion principle, 290 Oxindole, 426
MET kinase, 349 Neocarzinostatin, 314–317 Oxprenolol, 404
Me-too drugs, definition, 10 Neomycins, resistance to, 342 Oxyanion hole, 172–173
Metoprolol, 76, 373 Neoplasm, definition, 275–276 Oxygen rebound, 194–195
Mevastatin, 89f, 232 Neostigmine, 449–450 Oxyphenisatin, 430
Mevinolin, 232 Nerve cells, definition, 20–21
Mexiletin, 53–54 Nerve poison, 449
Minor groove, 279, 288–295 Neuraminidase, bound to zanamivir, 8 P
Minoxidil, 457 Neurokinin 1 (NK1) receptor, 150 p53, 275–276
Mitomycin C, 303–305 Neuroleptics, definition, 133–134 Paclitaxel, 91
Mix and split synthesis, 29–30 Neurotransmitters, definition, 20–21 PALA
Mixed function Neutral endopeptidase, in dual-acting enzyme multisubstrate analog, 223
oxidase, 365–366 inhibition, 230 synergism with, 349–350
oxygenases, 192–194 New drug application (NDA), 93 Pamidronate disodium, 23
Mizoribine definition, 14 Pantoprazole sodium, 444
prodrug, 350–351 Nicking, 281 Papain, 170, 198
synergism with, 350–351 Nicotinamide adenine dinucleotide, 184 Parallel synthesis, 29
Mlog P, 78–79 Nicotine, 379–380 Parecoxib sodium, 428
MOE, 40 (S)-Nicotine, 366–367 Parietal cell, 444
Molar volume, 84 Nicotinic acetylcholine receptors, 11 Paroxetine, 21–22
514 Index

Partial agonist, 152 oxidations of carbon–sulfur systems, Prednisolone, 403, 428–429

Partition coefficient, 75 385–387 Prednisolone phosphate, 429
Partition ratio, in mechanism-based enzyme oxidative aromatization, 387 Pregabalin, 10, 196–197, 393
inactivators, 247 oxidative dehalogenation, 387 P’ region, definition, 235–236
Pazopanib, 25t oxidative O-dealkylation, 385 Prilocaine, 140, 392
Penciclovir, 456 oxidative reactions, 365–388 Primaquine, 453–454
Penicillanic acid sulfone, 443 oxidative S-dealkylation, 385 Primaquine phosphate, 61
Penicillins, 3–4, 241–243 reductive dehalogenation, 391 Principen, 241
discovery of, 3 reductive reactions, 388–391 Principle of microscopic reversibility,
ideal drugs, 241–242 tertiary amine oxide reduction, 390–391 252–253
resistance to, 341–342, 346 Phase II metabolic transformations, 364, Privileged structures, definition, 34
structure of, 4 393–405 Probenecid, 370
synergism with, 347 acetyl conjugation, 400–403 Procainamide, 392
Penicillium chrysogenum, 4 amino acid conjugation, 398–399 Procaine, 392, 400
Penicillium notatum, 4 cholesterol conjugation, 403 Procarbazine, 448
Pentazocine, 55–56 fatty acid conjugation, 403 Prochiral, 184–186
Pentobarbital, 385 glucuronic acid conjugation, 395–397 pro-R, definition, 184–186
Pentostatin, 221–222 glutathione conjugation, 399–400 pro-S, definition, 184–186
synergism with, 348 methyl conjugation, 403–405 Prodrugs, 217, 358, 366
Pepsin, 198 polymorphism, 400–402 absorption and distribution, 424
Peptidases, definition, 21 procainamide, 400 aqueous solubility, 424
Peptide backbone isosteres, 70–71 sulfate conjugation, 397–398 bioprecursor prodrug, 424–425
Peptidoglycan transpeptidase, 174–175, water conjugation, 400 bioprecursor prodrugs, 443–458
241–242, 335f Phase III metabolism, 400 bipartite prodrug, 424
Peptidomimetics, 68–72 Phenacetin, 392, 398, 447 carrier-linked prodrugs, 424–443
definition, 68 Phenelzine sulfate, 247 codrugs, 443
Peptoids, 70–71 Phensuximide, 392–393 definition, 217, 366, 423
Perhexiline, 374 Phenylpropanolamine hydrochloride, 427 drug inactivation, mechanisms of,
Permeases, 442 Phenytoin, 371 425–458
Peroxisome proliferator-activated receptor Phosphatases, 393 to eliminate formulation problems, 435
(PPAR), 25t Phosphodiesterase-5, 6 to encourage patient acceptance, 435
Peroxisome proliferator-activated receptor 6-Phosphogluconate dehydrogenase (6PGDH), formulation problems, 424
gamma (PPARγ), 146 52–53 instability, 424
Pfeiffer’s rule, 140 Phosphoglycerate kinase, 455 macromolecular drug carrier systems,
P-glycoprotein, 89, 346, 350 Phosphoribosylpyrophosphate 435–438
Pharmacodynamics, 24 amidotransferase, 454–455 mechanism of drug, inactivation, 425–458
definition, 55, 123–124 Photolyases, 276 to minimize toxicity, 434–435
Pharmacokinetics, 24 Physiological pH, definition, 126 mutual prodrug, 424
in drug development, 217 Picoprazole, 444 mutual prodrugs, 443
Pharmacophore, 55–56 Pilocarpine, 124 poor patient acceptability, 424
Pharmacophore model, definition, 40 Pinocytosis, 436 prolonged release, 424
Pharmacophoric conformation, 147 π-π-interaction, 129–130 pro-soft drug, 423
Phase, 40 edge-to-face interaction, 129–130 site specificity, 424
Phase I metabolic transformations π-stacking, 129–130 for slow and prolonged release, 434
alcohol and aldehyde oxidations, 362, Pitch, 286 for stability, 433–434
387–388 Pivagabine, 126 toxicity, 424
aliphatic and alicyclic carbon atoms, Pivampicillin, 440, 443 tripartite prodrugs, 424, 438–443
oxidation at, 374–375 Plasmids, 281, 333 types of, 424–425
alkene epoxidation, 373 Plasmin, 170, 198 utility of, 424
aromatic hydroxylation, 368–373 Platelet-derived growth factor receptor Progabide, 427, 430
azido reduction, 390 (PDGFR) kinase, 214–216 Promazine, 61
azo reduction, 390 PLP, 178 Promethazine, 61
carbonyl reduction, 388–389 Polar surface area (PSA), definition, 33, 44 Promiscuous binders, definition, 34
carboxylation reaction, 391 Poly(α-amino acids), 436–437 Prontosil, 217
catechols, 387 Porphobilinogen synthase, in a problem, 199 Propanidid, 392
desulfuration, 385 Positive efficacy, 134–137 Propoxyphene, 377–378
effect of halogens on aromatic ring, 370 Potassium channels, 25t Propranolol, 141–142, 377, 433
hydrolytic reactions, 391–393 Potassium clavulanate, 443 S-(-)- and R-(+)-Propranolol, 364–365
nitro reduction, 389–390 Potency, 12 Propylthiouracil, 404–405
oxidations of carbon–nitrogen systems, definition, 12, 24 Prostacyclin synthase, 244
375–384 Pradefovir, 430–431 Prostaglandin H synthase, 367
oxidations of carbon–oxygen systems, 385 Pralidoxime chloride, 448 Prostaglandins (PGs) synthase, 208, 243–244,
oxidations of carbons adjacent to sp2 centers, Preclinical development, 13–14 384
373–374 Prednimustine, 403 inhibition for inflammation, 208
Index 515

Protease, 170, 208 Reaction constants, 73 SAR map, 58–59

cysteine proteases, 170 Reaction coordinate analogs, definition, 220 Saxagliptin, 234–235
serine proteases, 170, 172 Reaction specificity, 168 slow, tight-binding inhibitor of DPP-4,
threonine proteases, 170 Reactive Metabolites (RMs), 386–387, 405 234–235
Proteasome, 340 Receptor chirality, 140–146 Scaffold hopping, 43, 89–90
Protein engineering, definition, 197–198 Receptor-essential regions, 40 Scaffold peptidomimetics, 68–69
Protein kinase C (PKC), 91–92, 214–215 Receptor-excluded volume map, 40 Schiff base, 178
Protein microenvironment Receptor mapping, 40 Scopolamine, 2
effect on pKa, 81 Receptors Screening, definition, 11, 24
Proteome, 93–95 definition, 8–9 Screening of compounds
definition, 1 function, 124 drug-like and lead-like properties, 74
Proteomics, 93–95 fundamental characteristics, 124 medicinal chemistry collections, 27
definition, 1 Receptor tyrosine kinases (RTKs), 211–212 natural products, 26–27
Proton pump, 444 function, 123–124 random screening, 36
Pseudocholinesterase, 435 Rectal route, 357–358 sources of compounds for screening, 26–32
Pseudoephedrine, 2 Renin-angiotensin system, 225 targeted (or focused) screening, 36–43
Pseudohybrid drug, 142 Replication, 282 three-dimensional quantitative structure-
Pseudopeptides, 70–71 Repurposed drug, definition, 23 activity relationship (3D-QSARs), 38
p values, 73 Reserpine, 2 two-dimensional similarity models, 38
Pyridine nucleotide dependent enzyme, 184–188 Residence time, for an inhibitor, 225 virtual screening, 37–43
Pyridoxal 5′-Phosphate, 178–184 Reverse transcriptase, resistance to, 334 α-Secretases, 92
aminotransferases, 180–184 Reverse transcriptase inhibitor, 23 Selected ion monitoring, 363
α-cleavage, 186 Reversible DNA binders, 288–295 Selected reaction monitoring, 363
binding to protein, 178 groove binding, 289–290 Selective optimization of side activities
decarboxylases, 180 intercalators, 290–292 (SOSA), 54
β-elimination, 184 Reversible enzyme inhibitors Selective toxicity, 210, 219
racemases, 178–180 competitive reversible inhibitor, 210 of 5-fluorouracil, 257
reaction with aminoacid, 178 definition, 210 MPTP, 256
Pyrimethamine, 80–81 mechanism, 210–211 Selectivity, definition, 12–13
synergism with, 348 noncompetitive reversible inhibitor, 211 Selegiline, 254–256, 378–379, 457
Rho kinase, 25t Self-immolative prodrug. See Tripartite
Riboflavin, 189 prodrugs
Q
Ribonuclease A, 165 Sepiapterin reductase, 219
Quantitative structure–activity relationships
Ribonucleotide reductase, 247 Sequential simplex strategy, 86–87
(QSAR), 83–89
pentostatin effect on, 222 Serine hydroxymethyltransferase, 186
cluster analysis, 87
Ribose-1 phosphate uridine phosphorylase, 257 Serotonin reuptake inhibitors, 21–22
correlation of physicochemical parameters
Ring-chain transformations, 66–68 Sertraline, 391
with biological activity, 84–89
Ring topology, 151 σ receptor, 148
Craig plots, 86
Ritonavir, 235–238 Sildenafil citrate, 6
Ferguson’s principle, 83–84
lead discovery, 235–236 2D Similarity methods, 42
Fibonacci search method, 86
lead modification, 236–238 3D Similarity methods, 42
Hansch analysis, 84–85
resistance to, 335 Simvastatin, 232–234
physicochemical parameters, 83–84
synergism with, 348 Singletons, 43–44
sequential simplx strategy, 86
Rivastigmine, 22 siRNA, 9–10
steric effects, 83–84
Rivastigmine tartrate, 450 Sitagliptin phosphate, 197–198
three-dimensional, 39–41
Rofecoxib, 245, 385 Site-directed mutagenesis, 197–198
Topliss operational schemes, 85–87
Ronidazole, 454 Slow, tight-binding inhibitors, 225–235
Quiescent affinity labeling, 240
Rosiglitazone, 146 theoretical basis, 225
Quinidine, 374
Rosuvastatin, 89f Slow-binding inhibitors, definition, 225
Quinine, 3
Rotigotine, 11 Sodium valproate, 374
Quinone reductase, 389
R,S convention, 141–142 Soft drugs, 406
Rule of 3, 45–46 Solid-phase synthesis, definition, 27
R Rule of 5, 237 Solubility and bioavailability, 215
Rabeprazole, 444 properties, 32 Sorafenib, 30
Racemases, 178–180 SOSA, 53–54
Racemates as drugs, 143 S-Oxidation, 385–386
Racemic switch, 143
S
Specific catalysis, 170–171
σ,definition, 72–73
Radioactive compounds, synthesis of, 359–361 Specific radioactivity, 359–360
S-Adenosylmethionine (SAM), 188
Random screening, definition, 11 St. John’s wort, 366
pentostatin effect on, 222
Ranitidine, 155, 444 Staphylococcus aureus, 3–4
Salicylic acid, 127
Rasagiline, 254, 256, 378–379, 457 Statins, 232–234
SAR by MS, 49–50
Rate acceleration, 168 type 1 and type 2, 234
SAR by NMR, 46–48
Rate theory, 137 Stereoselectivity, 364–365
what is involved, 48
Rational drug design, definition, 1 Steric mapping, 40
SAR index, 58–59
516 Index

Steroid 5α-reductase, 231 T topomer CoMFA, 40

Strain/distortion, 173–174 Tacrine hydrochloride, 450 topomer similarity searching, 40
Streptokinase, 198 Tanimoto coefficient T, 38 weighted holistic invariant molecular
Structural alerts, 59 Target enzyme (WHIM), 40
Structurally nonspecific drugs, 57 definition, 208 Three-point attachment, 144–145
Structurally specific drugs, 57 desirable and undesirable properties, 208 distance geometry approach, 39
Structure–activity relationships, 57–59 ideal properties, 210 ensemble approach, 39
paclitaxel, 58–59 Targeted covalent inhibition, 241 Three-state receptor model, 139
sulpha drugs, 58 Targeted screening, definition, 11 Thromboxane synthase, 244
Structure-based de novo design, 42 Targeted therapy, definition, 211 Thymidine kinase, 257, 455
ligand-based approaches, 42 Targets validation, 9–10 Thymidylate synthase, 91, 247,
structure-based approaches, 42 Tariquidar, 350 257–259, 454
Structure-based model, definition, 40–41 synergism with, 350 synergism with, 348
Structure-based pharmacophore model, 40 Telenzepine, 149–150 Thymineless death, 257
Structure modification Teprotide, 226 Thyroid peroxidase, 247
bioisosterism, 62–66 Terazosin HCI, 231 Tienilic acid, 386–387
chain branching, 61–62 Terbutaline, 404 Tight-binding inhibitors, definition, 225
conformational constraints, 66–68 Terfenadine, 5, 358 Timoprazole, 444
electronic effects, 72–73 Tetrahydrofolate dependent enzyme, Tinidazole, 370
homologation, 60–61 184–188 Tirapazamine, 310–311
to increase oral bioavailability and membrane Thalidomide, 93, 140 Tissue plasminogen activator, 198
permeability, 72–83 Therapeutic index, definition, 59 Tivantinib, 349
to increase potency, therapeutic index and Thermodynamic activity, 83–84 Tobramycin, 342
ADME properties, 59–72 Thiopental, 385 Tolbutamide, 57
lipophilicity effects, 74–79 Thioridazine, 385–386 Tolerance, 333
peptidomimetics, 68–72 Three-dimensional quantitative structure- Tolmetin sodium, 434
ring-chain transformations, 66–68 activity relationship (3D-QSARs), Toltrazuril, 387
Sublingual route, 357–358 39–41 Topliss decision tree, 85
Substituent constant, 72–73 active analog approach, 40 Topliss operational schemes, 85–87
Substrate activity screening (SAS), 50–51 atom pair method, 39 Topoisomerase IIα, 339
Substructure search, 37–38 AutoDock, 41 Topoisomerase-induced DNA damage,
Subtilisin, 172–173 comparative binding energy analysis 290–292
Succinic semialdehyde dehydrogenase, 249 (COMBINE), 39–40 Topological torsion descriptor, 39
Suicide gene therapy, 432–433 comparative molecular field analysis Topomer, definition, 40
Sulfadimethoxine, 395 (CoMFA), 39–40 Topomer CoMFA, 40
Sulfadoxine, synergism with, 348 comparative molecular moment analysis Topomer similarity searching, 40
Sulfa drugs, 4, 58, 217–219 (CoMMA), 40 Topotecan hydrochloride, 291
lead discovery, 217 comparative molecular similarity indices Toxicophores, 59, 405
properties and activities, 58 analysis (CoMSIA), 39–40 Trametinib, synergism with, 349
resistance to, 341, 346 distance geometry approach, 39 Transcription, 281–282
side effects, 219 DOCK, 41 Transferases, 394
Sulfamethazine, 400–402 ensemble approach, 39 Transition state analogs, 219–225
Sulfamethoxazole, synergism with, 348 EVA, 40 enalaprilat, 220–221
Sulfanilamide, 217 Flex-S, 40 ideal enzyme target for, 220
folic acid biosynthesis, 218 Flex X, 41 pentostatin, 221–222
important scientific advance from, 217 Glide, 41 theoretical basis, 219–220
lead modification, 217 GOLD, 41 Transition state stabilization, 166
mechanism of action, 217–219 GRID, 41 Transition state theory, 166
Sulfapyridine, 390 GRIND, 40 Transporters, 346
Sulfasalazine, 390, 452 grid-independent descriptors (GRIND), function, 9
Sulfatases, 393 40 Triacetin, 435
Sulfisoxazole, 435 hologram QSAR, 40 Triazene antitumor drugs, 303
Sulfotransferase, 457 MolDock, 41 Triazolam, 446
Sulfotransferase-catalyzed sulfation, 397 molecular shape analysis, 39 Trifluridine, 247
Sulindac, 5, 453 multiple copy simultaneous search (MCSS), Trimeprazine, 61, 67
Sultamicillin, 443 41 Trimethoprim,
Sunitinib, 93–95 receptor-essential regions, 40 resistance to, 334
Super-coiled DNA, 281 receptor-excluded volume map, 40 synergism with, 348
Surflex, 41 receptor mapping, 40 Tripartite prodrugs, 424, 438–443
Surflex-sim, 40 steric mapping, 40 Tripeptide S, 309
Suvorexant structure-based de novo design, 42 Trypsin, 198
case history, 156–157 Surflex, 41 Turnover numbers, definition, 168
Synergism. See Drug synergism Surflex-sim, 40 Two dimensional similarity models, 38
Synthetic polymers, 436 topological torsion descriptor, 39 2D vs. 3D similarity methods, 42
Index 517

Two-state (multistate) model of receptor mechanism of action, 334 W

activation, 138–139 van der Waals/London dispersion forces, 130–131 Warfarin, 388
Tyramine effect, 458 Varenicline, 11 Weighted holistic invariant molecular (WHIM),
Tyrosine kinase, 48–49, 211–212, 427 Vascular endothelial growth factor receptor 2 40
kinase domain, 25t Wild-type enzyme, definition, 172–173
VDEPT. See Virus-directed enzyme prodrug
U
therapy (VDEPT)
Ubiquinone, 190
Veber rules, properties, 33
X
Ubiquitination, 340 Xanthine oxidase, 208, 247, 310–311,
Vedotin, 438
UDP-glucuronosyltransferase, 395 367, 389
VEGFR kinase, 349
Urease, 155, 165 inhibition for gout, 208
Verapamil, 143, 365
Uridine diphosphate-N- Xenobiotics, 192, 357
Verloop parameter, 84
acetylenolpyruvylglucosamine reductase, definition, 133
Vidarabine, 348, 453
192
Vigabatrin, 239, 430
Uridine kinase, 257
Uridine phosphorylase, 257
Virtual screening Z
database, 37 Zaleplon, 126
Urokinase, 198
definition, 36 Zanamivir, 90
Urokinase-type plasminogen activator, 54
HTS, 42 bound to neuraminidae, 8
hypothesis, 37–43 resistance to, 340
V Virus-directed enzyme prodrug therapy Zidovudine, 390
Valacyclovir, 456 (VDEPT), 433 Zidovudine, resistance to, 334
Valdecoxib, 245, 428 Vitamin deficiency, 178t Zinc ion, cofactor, 226–227
Valium, 132 Vitamins, 178f Zinostatin, 314–317
Vancomycin definition, 177t Zoledronic acid, 23