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Principles of Drug Design Full Toolbox Required for Success! Biological Discovery Biodisposition High Volume Screening Toxicity IND Lead Series Combinatorial Diversity Efficacy Rational [Structure, Design, Informatics] Pharmacokinetics Lead Discovery Research Iterative Process MEDC 603 Fall 2007 Preclinical R&D 1 Principles of Drug Design Lipinski’s Rule of Fives 1. 2. 3. 4. n-octanol H2O MW < 500 Fewer than five H-bond donating functions Fewer than 10 H-bond accepting functions Calculated logP (ClogP) between –1 and +5 P= [D]Lipid [D]Water GI Tract log P Vasculature (after absorption) MEDC 603 Fall 2007 2 Principles of Drug Design Lipinski’s Rule of Fives …. Examples O O CH3 COOH MW = 180 Da # H-bond donors = 1 # H-bond acceptors = 4 ClogP =2.44 Aspirin O H3C H3C O O O O CH3 MW = 282 Da # H-bond donors = 0 # H-bond acceptors = 5 ClogP =4.15 Artemisinin MEDC 603 Fall 2007 3 Principles of Drug Design Lipinski’s Rule of Fives …. Examples CH3 H3C N MW = 429 Da # H-bond donors = 1 C CCH3 # H-bond acceptors = 3 ClogP = 4.74 OH RU-486 O Amlodipine Cl H3COOC H3C COOCH2CH3 N H CH2OCH2CH2NH2 MW = 407.5 Da # H-bond donors = 3 # H-bond acceptors = 7 ClogP = -0.17 MEDC 603 Fall 2007 4 Principles of Drug Design General Approaches Pharmacophore ………an ensemble of steric and electronic features necessary to ensure the optimal supramolecular interactions with a specific biological target to trigger (or block) a biological response H H3C N OH H H H H3C N H3C N H3C N R O OH morphine OH morphinans MEDC 603 Fall 2007 OH benzomorphans OH 4-phenylpiperidines 5 Principles of Drug Design Chemical and Biochemical Isosteres Grimm’s Hydride Displacement Law C N O F Ne CH NH OH FH CH2 NH2 OH2 CH3 NH3 Hinsberg’s Ring Equivalents N N N NMe2 N NMe2 S Tripelennamine Methaphenilene MEDC 603 Fall 2007 Benzene, thiophene and pyridine are equivalent. e.g., H1-receptor antagonists … tripelennamine and methaphenilene 6 Principles of Drug Design Chemical and Biochemical Isosteres Friedman’s Bioisosteres …. chemical and physical properties OH OH HO F N N N HO Uracil ….. Fluorouracil (antineoplastic) N CONH2 COOH Salicylic acid ….. Salicamide (analgesic) OH OH CH3 OH OH Estradiol ….. Diethyl stilbestrol (estrogenic) HO HO MEDC 603 Fall 2007 7 Principles of Drug Design Lengthening Alkyl Chains Biological Activity 1. 2. 3. Increase hydrophobicity, decrease water solubility Increase conformational flexibility May be directly involved in interaction with receptor H N R H OH O Morphine OH R Chain Length ‘Normal’ Behavior -CH3 -CH2CH3 -CH2CH2CH3 -CH2CH2CH2CH3 -CH2CH2CH2CH2CH3 -CH2CH2CH2CH2CH2CH3 MEDC 603 Fall 2007 Activity Analgesic Agonist activity decreases Antagonist activity increases Inactive (agonist + antagonist) Antagonist activity increased Antagonist activity increased 8 Principles of Drug Design Flexibility of Drugs and Affinity Conf 1 GCONF R G Conf 2 = Bound Water = Free Water GOBS = GComplex + GSolv + GConf = -RT ln K MEDC 603 Fall 2007 9 Principles of Drug Design Dopamine Receptor Agonist HO HO HO HO OH OH OH OH N NMe2 NMe2 Me IV III II N Me I = dopamine receptor agonist II < III < IV < I MEDC 603 Fall 2007 10 Natural Products General ~25% of drugs in use today are derived from natural products 61% of the 877 NCE introduced between 1981 and 2002 can be traced to a natural product origin (J. Nat. Prod. (2003) 66:1022) In certain therapeutic areas, the impact is even higher, e.g., anticancer (74%) and anti-bacterial (78%) Yet, natural products was de-emphasized 20 years ago because of the advent of combinatorial chemistry! Combinatorial chemistry was not only faster and cheaper, but was much clearer with respect to intellectual property rights The alarming decline in the number of NCEs in the past years from an average of 30 per year to about 17 a year is correlated with decreased interest in natural products chemistry MEDC 603 Fall 2007 11 Natural Products General Natural products evolved for self-defense!! Amazing are the natural products that apparently evolved only for the purpose of alleviating our diseases, e.g., the statins Traditionally natural products are plant products, e.g., morphine from Papaver somniferum or digitoxin from Digitalis Plants form the bulk of natural product suppliers … current estimate of number of plant species on earth is ¼ million These days natural products are obtained from plants, algae, insects, bacteria, yeast, animals, …. MEDC 603 Fall 2007 12 Natural Products Advantages of Natural Products • • • • Evolution against challenges Structural diversity ‘Apparently’ unlimited quantity Potency Disadvantages of Natural Products • • • Synthesis Isolation Identification MEDC 603 Fall 2007 13 Natural Products Typically process of drug discovery from natural sources • • • • • • • • • Pre-knowledge helpful (cultural folklore, Chinese Materia Medica, Indian Ayurveda, ….) Collect source (plant, algae, animals, ….) Screen extracts (organic + aqueous extractions) HIT!! Chromatographic separation Screen individual components HIT or MISS?? Structural identification Independent synthesis and re-bioassay MEDC 603 Fall 2007 14 Natural Products Selected Examples of Natural Product derived Drugs O O CH3 CH3 H OH H3 C HO O H3C OH H3C O H OH O H OH O OH CH3 Digitoxin O CH3 H OH H3C HO OH O H3C H3C O H OH O OH Digoxin H Digitalis purpurea (Foxglove) and Digitalis lanata … long known for their healthy heart effects … exert a positive inotropic effect on cardiac muscles … treatment for heart failure MEDC 603 Fall 2007 15 Natural Products Selected Examples of Natural Product derived Drugs OCH3 OCH3 H OH H N N H Quinidine N N H OH Quinine Quinidine …bark of Cinchona tree …… anti-arrhythmic drug Quinine … no cardiac activity … anti-infective … malaria MEDC 603 Fall 2007 16 Natural Products Selected Examples of Natural Product derived Drugs MeO N N H H H H MeOOC O O OCH3 Reserpine OCH3 OCH3 OCH3 Reserpine …… alkaloid from Rauwolfia serpentina plant … lead from the Indian Ayurvedic system as good for heart ... used as anti-hypertensive … the plant was a source of ~20 different alkaloids … MEDC 603 Fall 2007 17 Natural Products Selected Examples of Natural Product derived Drugs HO HO O COO _ OH O R H3C H3C O CH3 O CH3 CH3 CH3 HO R Mevastatin R1 = R2 = H Lovastatin R1 = H; R2 = CH3 Simvastain R1 = R2 = CH3 Pravastatin …… fungal metabolites ... first fungal metabolite was compactin which inhibited HMGCoA reductase … compactin is isolated from Penicillium citrinum, Penicillium brevicompactin and Penicillium cyclopium ... an anti-fungal agent too, but toxic ... MEDC 603 Fall 2007 18 Natural Products Selected Examples of Natural Product derived Drugs O O O Warfarin O O CH3 * OH O O OH OH Dicoumarol Dicoumarol … … coumarin derivative … coumarin is widely distributed in nature … high concentrations in tonka beans (Dipteryx odorata) and also in Melitotus albus (sweet clover) … a hemorrhagic disorder was observed in animals that had consumed spoiled stuff composed of sweet clover … MEDC 603 Fall 2007 19 Natural Products Selected Examples of Natural Product derived Drugs _ CH2OSO3 COO _ NHSO3 O_ COO OH O OH OH OH O O OH _ CH2OSO3 _ CH2OSO3 CH2OH O O O _ _ NHSO3 O O_ COO OH O OH _ OSO3 O O NHCOCH3 O OH O OH _ NHSO3 Heparin … trying to find a coagulant ... accidentally found an anticoagulant! … structure took decades to come about … now we have low molecular weight heparin and heparin pentasaccharide … MEDC 603 Fall 2007 20 Natural Products Overview of Natural Products as Drugs Status in the Period 1981-2002 500 400 300 V = vaccines B = biologicals NP = natural products NPD = natural product derivatives SNP = synthetics derived from NP S = straight synthetics 200 100 0 V B NP NPD SNP S Compiled from : Newman, D. J., Cragg, G. M., and Snader, K. M. (2003) NATURAL PRODUCTS AS SOURCES OF NEW DRUGS OVER THE PERIOD 1981 – 2002. Journal of Natural Products 66, 1022-1037. MEDC 603 Fall 2007 21 Natural Products Structural Comparison between Natural Products and Combinatorial Compounds Combinatorial Compounds Data from Feher and Schmidt, J. Chem. Inf. Comput. Sci (2003) 43, 218. Natural Products Statistically defined chemical space is similar for natural products and drugs, while combinatorial compounds and drugs do not share similar space. Drugs MEDC 603 Fall 2007 22 Natural Products Current Efforts H3C H H CH 3 H3C CH3 HO OH Trinervitane derivative CH3 N H3C CH3 S Me Me Me O OH CH3 O OH Epothilone D O Nasute termites …. Soldier termites use their nozzle (squirt gun) to tangle up the invader in their toxic glue …. being developed by Entocosm, Australia as an antibiotic …. the natural product is 10 times less potent than a clinically practical antibiotic …. a potent ‘lead’ molecule Originally identified through synthesis … epoD was found to be produced by certain bacteria … genetic engineering … polyketide synthase gene knockout (epoD to epoB) … good yields … being developed by Kosan, CA as an antitumor (inhibition of microtubule formation) MEDC 603 Fall 2007 23