Transcript Structure-Activity Relationship and Natural Products

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
Research
Iterative
Process
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Preclinical
R&D
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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)
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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
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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
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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
H
H3C
N
OH
H
H
H
H3C
N
H3C
N
H3C
N
R
O
OH
morphine
OH
morphinans
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OH
benzomorphans
OH
4-phenylpiperidines
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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
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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

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
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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
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Activity
Analgesic
Agonist activity decreases
Antagonist activity increases
Inactive (agonist + antagonist)
Antagonist activity increased
Antagonist activity increased
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Principles of Drug Design
 Flexibility of Drugs and Affinity
Conf 1
GCONF
G
R
Conf 2
= Bound Water
= Free Water
GOBS = GComplex + GSolv + GConf = -RT ln K
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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
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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) 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
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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
O
O
CH3
CH3 H
OH
H3C
HO
O
H3C
OH
H3C
O
H
OH
O
H
OH
Digitoxin
O
OH
CH3
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
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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
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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 …
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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 ...
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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 …
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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 …
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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.
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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.
Natural Products
Statistically defined chemical space is
similar for natural products and drugs,
while combinatorial compounds and
drugs do not share similar space.
Drugs
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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)
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