Biological

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Principles of Drug Design

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Biological Discovery
Biodisposition
High Volume Screening
Toxicity
IND
Lead Series
Combinatorial Diversity
Efficacy
Rational Structure, Design, Informatics
Pharmacokinetics
Lead Discovery Iterative
Preclinical Research
Process RD
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Principles of Drug Design

• Lipinskis Rule of Fives

1. MW lt 500
2. Fewer than five H-bond donating functions
3. Fewer than 10 H-bond accepting functions
4. Calculated logP (ClogP) between 1 and 5

n-octanol
DLipid
P
log P
H2O
DWater
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Principles of Drug Design

• Lipinskis 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
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Principles of Drug Design

• Lipinskis 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
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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
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Principles of Drug Design

• Chemical and Biochemical Isosteres

• Grimms Hydride Displacement Law

C N O F Ne
CH NH OH FH
CH2 NH2 OH2
CH3 NH3

• Hinsbergs Ring Equivalents

Benzene, thiophene and pyridine are
equivalent. e.g., H1-receptor antagonists
tripelennamine and methaphenilene
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Principles of Drug Design

• Chemical and Biochemical Isosteres

• Friedmans Bioisosteres . chemical and
  physical properties

Uracil .. Fluorouracil (antineoplastic)
Salicylic acid .. Salicamide (analgesic)
Estradiol .. Diethyl stilbestrol (estrogenic)
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Principles of Drug Design

• Lengthening Alkyl Chains

1. Increase hydrophobicity, decrease water
   solubility
2. Increase conformational flexibility
3. May be directly involved in interaction with
   receptor

Morphine
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Principles of Drug Design

• Flexibility of Drugs and Affinity

DGOBS DGComplex DGSolv DGConf -RT ln K
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Principles of Drug Design

• Dopamine Receptor Agonist

II lt III lt IV lt I
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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) 661022)
• 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

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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,
  .

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Natural Products

• Advantages of Natural Products

• Evolution against challenges
• Structural diversity
• Apparently unlimited quantity
• Potency

• Disadvantages of Natural Products

• Synthesis
• Isolation
• Identification

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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

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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
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Natural Products

• Selected Examples of Natural Product derived Drugs

Quinidine bark of Cinchona tree
anti-arrhythmic drug Quinine no cardiac
activity anti-infective malaria
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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

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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
...
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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
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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
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Natural Products

• 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.
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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
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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)