bddd curriculum overview

8/14/2019 BDDD Curriculum Overview

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Basic drug design and discovery curriculum overview - January 2010

Section and subject Page1.3 What kind of compounds become drugs? 7

Oral administration Lipinskis rule of five 7Cellular uptake 81.6 Lead Optimization 26ADME 26Absorption 26Metabolism 26Proteinbinding 27Distribution 27-28Excretion 28Pharmacophore 28Drug development challenges 29Bioisterism 30

2.3 The physical basis of intermolecular interactions 37Electrostatic interactions 37Ionic bonds 37Charge-dipole and dipole-dipole interactions 37Ion-quadrupole and dipole-quadrupole 38Dispersion forces (London Forces) 38Hydrogen bonds 39Steric interactions 39

Translational and rotational entropy 41Hydrophobic effect 41Solvent reorganization 42

Stereochemistry in drug design3.1 Introduction 533.2 What are stereoisomers? 54Optical isomers Chirality 54Optical rotation Levorotatory/Dextrorotatory 56Sequence rules R/S 57Diastereomers 58

Meso compounds 583.3 The origin of stereospecificity in molecular recognition 59Induced fit model 59Three-point receptor theory 603.4 Why is stereochemistry important in drug design? 61Fluoxetine 62Thalidomide 63Eudismic Ratio Eutomer/Distomer 63Examples Different eneantiomer relationships 63-673.5 Methods of obtaining pure stereoisomers 67Resolution of racemates by crystallization 68Enantioselective chromatography 70


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Ligand exchange chromatography 71Crown ether 71Asymmetric synthesis 74Chiral pool 75

Chiral auxiliary 75Chiral reagents and chiral catalysts 77L-DOPA 78

Receptors: Structure, function and pharmacology 1566.1 Introduction 156Receptors GPCR, ligand-gated ion channels, tyrosine kinase receptors and nuclear receptors 156Synapses and neurotransmitters 158Agonists, partial agonists and antagonists effect on receptor sensitivity 1596.2 Receptor structure and function 159Receptor location 159G-protein coupled receptors 160Subfamilies of GPCR 160Ligand-gated ion channel receptors 162Hyper/hypopolarisation 162Nicotinic acetylcholine receptor 162Tyrosine Kinase receptors Integral TK and Janus Kinase 164Autophosphorylation 165Nuclear receptors 1666.3 Receptor pharmacology 168Binding assays and functional assays 168

Fluorometric imaging plate reader 168Agonists Potenty and maximal response 169Antagonists 170Cheng-Prusoff equation Schild analysis 170Allosteric modulators 171Note Positive allosteric modulatorsEvidence of allosteric mechanism and orthosteric binding pockets 2Advantages of allosteric modulators 2Inverse agonism 3

Ion channels: Structure, function and pharmacology 173

7.1 Introduction 173Excitable cells 173Ion distribution across cell membrane 173Negative interior 174Ion distribution 174Patch clamp 1777.2 Structure and function of ion channels 178Ion channel characteristics 178Voltage gated and ligand gated ion channels 180GABA-gated Cl - -channel 182Nicotinic acetylcholine receptor channel 1827.3 The classification of ion channels 183


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Classification by drug action 185Classification of voltage gated Ca 2+ channels 187Classification of K + channels 1877.4 Ion channels as pharmacological receptors 188

States of ion channels 188Structure-activity relationships 1917.5 Drugs acting at specific ion channels 193Drugs acting at Na + channels 193Conotoxins 194Drugs acting at Ca 2+ channels 196L-type Ca 2+ channels 196Drugs acting at K + channels 200Scorpion toxins 200Sulfonylurea receptors 2007.6 Ion channels and diseases 2017.7 Ion channels as lethal species 2037.8 Future developments 203

Excitatory and inhibitory amino acid receptor ligands 2329.1 Therapeutic prospects for excitatory and inhibitory amino acids 232Neurodegenerative disorders 232Alzheimers disease 233Anxiety, pain and schizophrenia 2349.2 GABA: Inhibitory neurotransmitter 235GABA targets: receptor a(nta)gonism, allosteric modulation, interference reuptake/metabol 236

Muscimol 236GABA biosynthesis and metabolism 238GABA-transaminase inhibitors 238Vigabatrin 238GABA uptake transporters and cotransport 241GABA uptake inhibitors 241Tiagabine 242GABA receptors Ionotropic (GABA A and GABAC) and GPCR (GABAB) 244GABAA receptor comple and ligands 246Benzodiazepines and neurosteroids 248GABAB receptor ligands 251

GABAC receptor ligands 2539.3 Glutamic acid: Excitatory neurotransmitter and excitotoxin 253Classification and ligands for glutamate receptors 254Ionotropic receptors: NMDA, AMPA and Kain receptors 254-255Metabotropic glutamate receptors 254-255Structure of ionotropic glutamate receptors 255NMDA receptor ligands Glycine co-agonist Mg2+ blockade 255-258AMPA receptor ligands 258Kain receptor ligands 259Structure of metabotropic glutamate receptors - Three groups 260Metabotropic glutamate receptor ligands HIBO analogs 261Ibotenic acid Excitotoxin and lead structure 263


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5-Substituted AMPA analogs 264Isoxazole based AMPA receptor antagonists 266Homoibotenic acid analogs as metabotropic antagonists 2679.4 Future developments 270

Acetylcholine and histamine receptors and receptor ligands: medicinal chemistry andtherapeutic approaches

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10.1 Alzheimers disease 27210.2 Cholinergic synaptic mechanisms as therapeutic targets 274Acetyl-CoA:choline-O-acetyltransferase 274Inhibitory control 275Positive feed-back regulation 276Muscarinic and nicotinic acetylcholine receptors and receptor ligands 276Muscarinic receptor subtypes m 1-m 5 277Nicotinic receptor subunits 279Muscarinic antagonists 279Anatomical locations of mAchR subtypes 280Muscarinic agonists and partial agonists 282Nicotinic agonists and partial agonists 288Acetylcholinesterase inhibitors 290AchE inhibitor classes: Irreversible organophosphorus inhibitors and carbamoylating rev inh 29110.3 Histamine receptors 292GPCR H1, H2, H3 and H 4 292H1 receptor antagonists 293Pre / Postsynaptic localization of histamine receptors 293H

2and H

3receptor antagonists 294

Cimetidine 296

Dopamine and serotonin receptor and transporter ligands 29911.1 Receptors and transporters for dopamine and serotonin 299Postsynaptic receptors and autoreceptors 29911.2 Dopamine and serotonin receptor ligands 300DA and serotonin receptor subtypes 300-302Antipsychotic drugs 302Classical (Typical) antipsychotics: Reserpine and chlorpromazine 302Dopamine hypothesis of schizophrenia Methylphenidate in vitro model 303

New (Atypical) antipsychotics: Clozapine, risperidone, quetiapine and Olanzapine 306Receptor profile of antipsychotic drugs 307Development of antipsychotics at Lundbeck 308-31011.3 Dopamine and serotonin transporter ligands 312Transporter structures 313Antidepressant drugs 314TCA and MAO inhibitors 314-315SSRI 316-321Fluoxetine, citalopram, sertraline 318SSRI interaction with CYP450 319Serotonin pharmacophore model 320Dopamine uptake inhibitors 323


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Enzymes and enzyme inhibitors 32812.1 Introduction 328Enymatic catalysis 328

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

12.4 Other types of inhibitors 356Slow, tight-binding inhibitors COX2 inhibitors 356-358Covalent enzyme modifiers 358-360Mechanism-based enzyme inhibitors 360

Metals in medicine: inorganic medicinal chemistry 36413.1 Introduction 364Essential and non-essential elements 36513.2 Classification of inorganic pharmaceuticals 367Active complexes 367Active elements 368

Active ligands 36813.2 The human body and bioinorganic chemistry 368Abundance of elements in the body 368Chelate therapy 37013.4 Coordination chemistry 371Chelate effect 371Ligand types 371Irving-Williams series 372Hard and soft acids and bases Class a metals and Class b metals 373Labile, stable and inert complexes 375Crystal field splitting 375High-spin complexes and low-spin complexes 375


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Spectrochemical series Strong-field ligands and weak-fields ligands 376Crystal fields stabilization energy 376Redox reactions 377Trans-effect Cisplatin 378

Plasma mobilization index 38013.5 Chelate therapy 38213.6 Selected chelates 383BAL D-penicillamine and EDTA 383Desferrioxamine 38513.7 Drug-metal ion interaction 385Tetracycline 38613.8 Inorganic chemistry and pharmaceuticals 386Alkali metals sodium and potassium 387Lithium 389Alkaline earth metals Magnesium, calcium and barium 389Chromium, Vanadium and molybdenum 391Iron and cobal 392Bleomycin and nitroprusside 396B12 397Platinum and ruthenium 398Copper, silver and gold 399Albumin 403Zinc, cadmium and mercury 404Zinc finers 405Antimony and bismuth 407

Design and application of prodrugs 41014.1 The prodrug concept 410Barriers to drug action 41114.2 Choice and function of the pro-moiety 413Stability of prodrugs in different pH 415Modification of physicochemical properties Lipophilicity and solubility 417 423Phenytoin 419 4205-Fluorouracil 421 422Anticancer and drug transport 42414.3 Bioreversible derivatives for various functioncal groups 426

Esters as prodrug for compounds containing carboxyl or hydroxyl groups 428Prodrugs of metronidazole 428Prodrug for amides, imides and NH-acidic compounds 430N-Mannich bases 430Tetracycline 432Hetacillin 433N-a-acyloxyalkyl derivatives Secondary amindes, imides, hydantoins uracils 433N-acyl derivatives 434Carbimazole 435Prodrugs for amines Amides, N-acyloxyalkylcarbonyl derivatives and N-Mannich bases 435 437Prodrugs for carbonyl groups Oxazolidines and thiazolidines 437Prodrugs of corticosteroids 438


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Alkylating agents 513Nitrogen mustards 513DNA crosslinking 514Chlorambucil, melphalan, cyclophosphamide 516

Aziridines Thiotepa 518Nitrosureas Carmustine, streptozotocin 519Triazenes Dacarbazine 520Hydrazines Procarbazine 522Methanesulphonate esters Busulphan 522Metal complex binding to DNA 522Platin complexes Cisplatin, carboplatin, oxaliplatin 523 526Degradation of DNA Bleomycin 526Intercalating agents 528Actinomycin 529Daunorubicin, doxorubicin and analogs 531 536

Antisense agents 536Inhibition of tetrahydrofolate synthesis Methotrexate 537 542Inhibition of purine and pyrimidine synthesis 6-Mercaptopurine and fluorouracil 542 544Inhibition of DNA/RNA polymerases Cytarabine 547Inhibition of ribonucleotide reductase Hydroxyurea 54817.2 Mitotic apparatus as target for drugs 550Drugs interfering with the Vinca alkaloid binding site of tubulin - Vinblastine and vincristine 550 553Drugs interfering with the colchicines binding site of tubulin Podophyllotoxin and Colchicin 553Drugs stabilizing the assembly of tubulin into microtubules Paclitaxel 554 - 556

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

bddd curriculum overview

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