1. 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

2. 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

3. 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

4. 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 = Da
# H-bond donors = 3
# H-bond acceptors = 7
ClogP = -0.17
MEDC 603 Fall 2007

5. 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

6. 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

7. 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

8. 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

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

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

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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

20. 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

21. Natural Products V B NP NPD SNP S
Overview of Natural Products as Drugs Status in the Period
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 – Journal of Natural Products 66,
MEDC 603 Fall 2007

22. 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

23. 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