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 Iterative Preclinical Research Process R&D MEDC 603 Fall 2007

Principles of Drug Design Lipinski’s Rule of Fives MW < 500 Fewer than five H-bond donating functions Fewer than 10 H-bond accepting functions Calculated logP (ClogP) between –1 and +5 n-octanol [D]Lipid P = log P H2O [D]Water GI Tract Vasculature (after absorption) MEDC 603 Fall 2007

Principles of Drug Design Lipinski’s Rule of Fives …. Examples MW = 180 Da # H-bond donors = 1 # H-bond acceptors = 4 ClogP =2.44 Aspirin MW = 282 Da # H-bond donors = 0 # H-bond acceptors = 5 ClogP =4.15 Artemisinin MEDC 603 Fall 2007

Principles of Drug Design Lipinski’s Rule of Fives …. Examples MW = 429 Da # H-bond donors = 1 # H-bond acceptors = 3 ClogP = 4.74 RU-486 Amlodipine MW = 407.5 Da # H-bond donors = 3 # H-bond acceptors = 7 ClogP = -0.17 MEDC 603 Fall 2007

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 MEDC 603 Fall 2007

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 Benzene, thiophene and pyridine are equivalent. e.g., H1-receptor antagonists … tripelennamine and methaphenilene MEDC 603 Fall 2007

Principles of Drug Design Chemical and Biochemical Isosteres Friedman’s Bioisosteres …. chemical and physical properties Uracil ….. Fluorouracil (antineoplastic) Salicylic acid ….. Salicamide (analgesic) Estradiol ….. Diethyl stilbestrol (estrogenic) MEDC 603 Fall 2007

Principles of Drug Design Lengthening Alkyl Chains Increase hydrophobicity, decrease water solubility Increase conformational flexibility May be directly involved in interaction with receptor Biological Activity Chain Length ‘Normal’ Behavior Morphine MEDC 603 Fall 2007

Principles of Drug Design Flexibility of Drugs and Affinity = Bound Water = Free Water DGOBS = DGComplex + DGSolv + DGConf = -RT ln K MEDC 603 Fall 2007

Principles of Drug Design Dopamine Receptor Agonist II < III < IV < I MEDC 603 Fall 2007

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., anti-cancer (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

Natural Products Natural products evolved for self-defense!! 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

Natural Products Evolution against challenges Structural diversity Advantages of Natural Products Evolution against challenges Structural diversity ‘Apparently’ unlimited quantity Potency Disadvantages of Natural Products Synthesis Isolation Identification MEDC 603 Fall 2007

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

Natural Products Selected Examples of Natural Product derived Drugs 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

Natural Products Selected Examples of Natural Product derived Drugs Quinidine …bark of Cinchona tree …… anti-arrhythmic drug Quinine … no cardiac activity … anti-infective … malaria MEDC 603 Fall 2007

Natural Products Selected Examples of Natural Product derived Drugs 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

Natural Products Selected Examples of Natural Product derived Drugs …… fungal metabolites ... first fungal metabolite was compactin which inhibited HMG-CoA reductase … compactin is isolated from Penicillium citrinum, Penicillium brevicompactin and Penicillium cyclopium ... an anti-fungal agent too, but toxic ... MEDC 603 Fall 2007

Natural Products Selected Examples of Natural Product derived Drugs Warfarin 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

Natural Products Selected Examples of Natural Product derived Drugs 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

Natural Products V B NP NPD SNP S Overview of Natural Products as Drugs Status in the Period 1981-2002 V = vaccines B = biologicals NP = natural products NPD = natural product derivatives SNP = synthetics derived from NP S = straight synthetics 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

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. Statistically defined chemical space is similar for natural products and drugs, while combinatorial compounds and drugs do not share similar space. Natural Products Drugs MEDC 603 Fall 2007

Natural Products Current Efforts 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