Basic drug design and discovery curriculum overview - January 2010

Section and subject Page

1.3 What kind of compounds become drugs? 7
Oral administration – Lipinskis rule of five 7
Cellular uptake 8
1.6 Lead Optimization 26
ADME 26
Absorption 26
Metabolism 26
Proteinbinding 27
Distribution 27-28
Excretion 28
Pharmacophore 28
Drug development challenges 29
Bioisterism 30

2.3 The physical basis of intermolecular interactions 37

Electrostatic interactions 37
Ionic bonds 37
Charge-dipole and dipole-dipole interactions 37
Ion-quadrupole and dipole-quadrupole 38
Dispersion forces (London Forces) 38
Hydrogen bonds 39
Steric interactions 39
Translational and rotational entropy 41
Hydrophobic effect 41
Solvent reorganization 42

Stereochemistry in drug design

3.1 Introduction 53
3.2 What are stereoisomers? 54
Optical isomers – Chirality 54
Optical rotation – Levorotatory/Dextrorotatory 56
Sequence rules – R/S 57
Diastereomers 58
Meso compounds 58
3.3 The origin of stereospecificity in molecular recognition 59
Induced fit model 59
Three-point receptor theory 60
3.4 Why is stereochemistry important in drug design? 61
Fluoxetine 62
Thalidomide 63
Eudismic Ratio – Eutomer/Distomer 63
Examples – Different eneantiomer relationships 63-67
3.5 Methods of obtaining pure stereoisomers 67
Resolution of racemates by crystallization 68
Enantioselective chromatography 70

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Ligand exchange chromatography 71
Crown ether 71
Asymmetric synthesis 74
Chiral pool 75
Chiral auxiliary 75
Chiral reagents and chiral catalysts 77
L-DOPA 78

Receptors: Structure, function and pharmacology 156

6.1 Introduction 156
Receptors GPCR, ligand-gated ion channels, tyrosine kinase receptors and nuclear receptors 156
Synapses and neurotransmitters 158
Agonists, partial agonists and antagonists effect on receptor sensitivity 159
6.2 Receptor structure and function 159
Receptor location 159
G-protein coupled receptors 160
Subfamilies of GPCR 160
Ligand-gated ion channel receptors 162
Hyper/hypopolarisation 162
Nicotinic acetylcholine receptor 162
Tyrosine Kinase receptors – Integral TK and Janus Kinase 164
Autophosphorylation 165
Nuclear receptors 166
6.3 Receptor pharmacology 168
Binding assays and functional assays 168
Fluorometric imaging plate reader 168
Agonists – Potenty and maximal response 169
Antagonists 170
Cheng-Prusoff equation – Schild analysis 170
Allosteric modulators 171
Note Positive allosteric modulators
Evidence of allosteric mechanism and orthosteric binding pockets 2
Advantages of allosteric modulators 2
Inverse agonism 3

Ion channels: Structure, function and pharmacology 173

7.1 Introduction 173
Excitable cells 173
Ion distribution across cell membrane 173
Negative interior 174
Ion distribution 174
Patch clamp 177
7.2 Structure and function of ion channels 178
Ion channel characteristics 178
Voltage gated and ligand gated ion channels 180
GABA-gated Cl- -channel 182
Nicotinic acetylcholine receptor channel 182
7.3 The classification of ion channels 183

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Classification by drug action 185
Classification of voltage gated Ca2+ channels 187
Classification of K+ channels 187
7.4 Ion channels as pharmacological receptors 188
States of ion channels 188
Structure-activity relationships 191
7.5 Drugs acting at specific ion channels 193
Drugs acting at Na+ channels 193
Conotoxins 194
Drugs acting at Ca2+ channels 196
L-type Ca2+ channels 196
Drugs acting at K+ channels 200
Scorpion toxins 200
Sulfonylurea receptors 200
7.6 Ion channels and diseases 201
7.7 Ion channels as lethal species 203
7.8 Future developments 203

Excitatory and inhibitory amino acid receptor ligands 232

9.1 Therapeutic prospects for excitatory and inhibitory amino acids 232
Neurodegenerative disorders 232
Alzheimers disease 233
Anxiety, pain and schizophrenia 234
9.2 GABA: Inhibitory neurotransmitter 235
GABA targets: receptor a(nta)gonism, allosteric modulation, interference reuptake/metabol 236
Muscimol 236
GABA biosynthesis and metabolism 238
GABA-transaminase inhibitors 238
Vigabatrin 238
GABA uptake transporters and cotransport 241
GABA uptake inhibitors 241
Tiagabine 242
GABA receptors – Ionotropic (GABAA and GABAC) and GPCR (GABAB) 244
GABAA receptor comple and ligands 246
Benzodiazepines and neurosteroids 248
GABAB receptor ligands 251
GABAC receptor ligands 253
9.3 Glutamic acid: Excitatory neurotransmitter and excitotoxin 253
Classification and ligands for glutamate receptors 254
Ionotropic receptors: NMDA, AMPA and Kain receptors 254-255
Metabotropic glutamate receptors 254-255
Structure of ionotropic glutamate receptors 255
NMDA receptor ligands – Glycine co-agonist – Mg2+ blockade 255-258
AMPA receptor ligands 258
Kain receptor ligands 259
Structure of metabotropic glutamate receptors - Three groups 260
Metabotropic glutamate receptor ligands – HIBO analogs 261
Ibotenic acid – Excitotoxin and lead structure 263

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5-Substituted AMPA analogs 264
Isoxazole based AMPA receptor antagonists 266
Homoibotenic acid analogs as metabotropic antagonists 267
9.4 Future developments 270

Acetylcholine and histamine receptors and receptor ligands: medicinal chemistry and 272
therapeutic approaches
10.1 Alzheimers disease 272
10.2 Cholinergic synaptic mechanisms as therapeutic targets 274
Acetyl-CoA:choline-O-acetyltransferase 274
Inhibitory control 275
Positive feed-back regulation 276
Muscarinic and nicotinic acetylcholine receptors and receptor ligands 276
Muscarinic receptor subtypes m1-m5 277
Nicotinic receptor subunits 279
Muscarinic antagonists 279
Anatomical locations of mAchR subtypes 280
Muscarinic agonists and partial agonists 282
Nicotinic agonists and partial agonists 288
Acetylcholinesterase inhibitors 290
AchE inhibitor classes: Irreversible organophosphorus inhibitors and carbamoylating rev inh 291
10.3 Histamine receptors 292
GPCR H1, H2, H3 and H4 292
H1 receptor antagonists 293
Pre / Postsynaptic localization of histamine receptors 293
H2 and H3 receptor antagonists 294
Cimetidine 296

Dopamine and serotonin receptor and transporter ligands 299

11.1 Receptors and transporters for dopamine and serotonin 299
Postsynaptic receptors and autoreceptors 299
11.2 Dopamine and serotonin receptor ligands 300
DA and serotonin receptor subtypes 300-302
Antipsychotic drugs 302
Classical (Typical) antipsychotics: Reserpine and chlorpromazine 302
Dopamine hypothesis of schizophrenia – Methylphenidate in vitro model 303
New (Atypical) antipsychotics: Clozapine, risperidone, quetiapine and Olanzapine 306
Receptor profile of antipsychotic drugs 307
Development of antipsychotics at Lundbeck 308-310
11.3 Dopamine and serotonin transporter ligands 312
Transporter structures 313
Antidepressant drugs 314
TCA and MAO inhibitors 314-315
SSRI 316-321
Fluoxetine, citalopram, sertraline 318
SSRI interaction with CYP450 319
Serotonin pharmacophore model 320
Dopamine uptake inhibitors 323

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Enzymes and enzyme inhibitors 328
12.1 Introduction 328
Enymatic catalysis 328
12.1 Checmical mechanisms of enzyme catalysis 329
Alters rate – Not thermodynamic favorability 330
Transition state 330
Activation energy 331
Michaelis Menten kinetics 333
Lineweveaer-Burk plots 334
Enzyme – substrate interactions 335
Approximation 336
Covalent catalysis 337-339
Acid/base chemistry in enzymes 339
Conformational distortions 340
Reversible enzyme inhibitors 342
Competitive inhibition – Exclusively binding to the free enzyme 342
Langmuir isotherm 344
Dihydrofolate reductase – Methotrexate and trimethoprim 346
HMG-CoA reductase inhibitors – Statins 348
ACE inhibitors – Captopril and enalapril 349
Non-competitive inhibition – Binding affinity for the free enzyme and ES complex 350
NNRTIs – Nevirapine and efavirenz – Binding close to active site 351-354
Uncompetitive inhibition – Binds exclusively to the ES complex 354
Steroid 5 -reductase inhibitor – Epristeride 355
12.4 Other types of inhibitors 356
Slow, tight-binding inhibitors – COX2 inhibitors 356-358
Covalent enzyme modifiers 358-360
Mechanism-based enzyme inhibitors 360

Metals in medicine: inorganic medicinal chemistry 364

13.1 Introduction 364
Essential and non-essential elements 365
13.2 Classification of inorganic pharmaceuticals 367
Active complexes 367
Active elements 368
Active ligands 368
13.2 The human body and bioinorganic chemistry 368
Abundance of elements in the body 368
Chelate therapy 370
13.4 Coordination chemistry 371
Chelate effect 371
Ligand types 371
Irving-Williams series 372
Hard and soft acids and bases – Class a metals and Class b metals 373
Labile, stable and inert complexes 375
Crystal field splitting 375
High-spin complexes and low-spin complexes 375

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Spectrochemical series – Strong-field ligands and weak-fields ligands 376
Crystal fields stabilization energy 376
Redox reactions 377
Trans-effect – Cisplatin 378
Plasma mobilization index 380
13.5 Chelate therapy 382
13.6 Selected chelates 383
BAL – D-penicillamine and EDTA 383
Desferrioxamine 385
13.7 Drug-metal ion interaction 385
Tetracycline 386
13.8 Inorganic chemistry and pharmaceuticals 386
Alkali metals – sodium and potassium 387
Lithium 389
Alkaline earth metals – Magnesium, calcium and barium 389
Chromium, Vanadium and molybdenum 391
Iron and cobal 392
Bleomycin and nitroprusside 396
B12 397
Platinum and ruthenium 398
Copper, silver and gold 399
Albumin 403
Zinc, cadmium and mercury 404
Zinc finers 405
Antimony and bismuth 407

Design and application of prodrugs 410

14.1 The prodrug concept 410
Barriers to drug action 411
14.2 Choice and function of the pro-moiety 413
Stability of prodrugs in different pH 415
Modification of physicochemical properties – Lipophilicity and solubility 417 – 423
Phenytoin 419 – 420
5-Fluorouracil 421 – 422
Anticancer and drug transport 424
14.3 Bioreversible derivatives for various functioncal groups 426
Esters as prodrug for compounds containing carboxyl or hydroxyl groups 428
Prodrugs of metronidazole 428
Prodrug for amides, imides and NH-acidic compounds 430
N-Mannich bases 430
Tetracycline 432
Hetacillin 433
N-a-acyloxyalkyl derivatives – Secondary amindes, imides, hydantoins uracils 433
N-acyl derivatives 434
Carbimazole 435
Prodrugs for amines – Amides, N-acyloxyalkylcarbonyl derivatives and N-Mannich bases 435 – 437
Prodrugs for carbonyl groups – Oxazolidines and thiazolidines 437
Prodrugs of corticosteroids 438

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Drug activation from intramolecular cyclization reactions 438
Pilocaripine 438
14.4 Applications of the prodrug approach 444
Ampicillin derivatives – Pivampicillin and bacampicillin 444
Diazepam prodrugs 446
Dermal absorption – Levonorgestrel and nalidixic acid 446 – 446
Ocular absorption – Epinephrine 447 – 448
Prevention of first-pass metabolism – Naltrexone, testosterone, terbutaline 448 – 451
Site specific bioactivation – Acyclovir, omeprazole, sulfasalazine 452 – 454
Improved drug formulation – dinoprostone, fluphenazine (neuroleptics) 454 – 455
Sulphate esters and hemisuccinate esters – Corticosteroids, chloramphenicol, metronidazol 456
Loxapine 457

Peptides and peptidomimetics 459

15.1 Introduction 459
L-configurated natural amino acids 459
15.2 Strategies for peptidomimetic drug discovery 465
Succesfull peptidomimetic: Oral bioavailability, receptor affinity and selectivity, few AE 466
Farmer’s rules for converting peptide to peptidomimetic 466
Amino acid manipulations – Ala scan, phenylalanine scan, conformational constraints 467
Peptide backbone modifications – Amide bond replacement 467
- and turn mimetics and -helix and -sheet mimetics 471
ACE-inhibitors 475
Cholecystokinin receptor ligands 475
Arginine vasopressin receptor ligands and bradykinin receptor ligands 477
Mimetics of GHRH 478
Small molecule insulin mimetics 481

Classical antiviral agents and design of new antiviral agents 486

16.1 Classical antiviral agents 486
5-iodo-2’-deoxyuridine, zidovudine 487
Nucleosides and nucleoside analogs as antiherpes agents 488
Varicella zoster 489
Acyclovir and ganciclovir 492
Ribavirin 493
Nucleoside reverse transcriptase inhibitors 494
Non-nucleoside reverse transcriptase inhibitors 496
Protease inhibitors 497
16.2 Design of new antiviral agents 500
Analogs of 5’-monophosphates and prodrugs 502
Nucleosides with L-configuration 504
Amantadine, rimantadine, neuranamidase inhibitors and interferons 505
New anti-HIV drugs – Fusion inhibitors, integrase inhibitors 507 – 510

Anticancer agents 511

17.1 DNA as target for anticancer drugs 511
Lack of selectivity 511
Multidrug resistance 512

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Alkylating agents 513
Nitrogen mustards 513
DNA crosslinking 514
Chlorambucil, melphalan, cyclophosphamide 516
Aziridines – Thiotepa 518
Nitrosureas – Carmustine, streptozotocin 519
Triazenes – Dacarbazine 520
Hydrazines – Procarbazine 522
Methanesulphonate esters – Busulphan 522
Metal complex binding to DNA 522
Platin complexes – Cisplatin, carboplatin, oxaliplatin 523 – 526
Degradation of DNA – Bleomycin 526
Intercalating agents 528
Actinomycin 529
Daunorubicin, doxorubicin and analogs 531 – 536
Antisense agents 536
Inhibition of tetrahydrofolate synthesis – Methotrexate 537 – 542
Inhibition of purine and pyrimidine synthesis – 6-Mercaptopurine and fluorouracil 542 – 544
Inhibition of DNA/RNA polymerases – Cytarabine 547
Inhibition of ribonucleotide reductase – Hydroxyurea 548
17.2 Mitotic apparatus as target for drugs 550
Drugs interfering with the Vinca alkaloid binding site of tubulin - Vinblastine and vincristine 550 – 553
Drugs interfering with the colchicines binding site of tubulin – Podophyllotoxin and Colchicin 553
Drugs stabilizing the assembly of tubulin into microtubules – Paclitaxel 554 - 556

Biochemistry
The Nature of Noncovalent interactions 27
Charge – charge interactions 27
Coulombs law – Dielectric medium and dielectric constant 27
Types of noncovalent interactions 28
Permanent dipoles 29
Polarizable molecules 30
Van der Waals radius 31 – 32
Hydrogen bonds – Acceptors and donors 31 – 33
Bond lengths 32