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PURVI H. KAKRANI, SPSRC, VALASAN
1
Biological Discovery
High VolumeScreening
CombinatorialDiversity
Rational[Structure, Design,
Informatics]
Lead Series
Biodisposition
Toxicity
Efficacy
Pharmacokinetics
INDIND
Lead Discovery Iterative PreclinicalResearch Process R&D
Principles of Drug Design
Full Toolbox Required for Success!
05/02/23
PURVI H. KAKRANI, SPSRC, VALASAN
2
Principles of Drug Design
Lipinski’s Rule of Fives
1. MW < 5002. Fewer than five H-bond donating functions3. Fewer than 10 H-bond accepting functions4. Calculated logP (ClogP) between –1 and +5
H2O
n-octanolP = [D]Lipid
[D]Waterlog P
GI Tract Vasculature(after absorption)
05/02/23
PURVI H. KAKRANI, SPSRC, VALASAN
3
Lipinski’s Rule of Fives …. Examples
Principles of Drug Design
O
O
CH3
COOH
MW = 180 Da# H-bond donors = 1# H-bond acceptors = 4ClogP =2.44
O
OO
CH3CH3
CH3
O
O
MW = 282 Da# H-bond donors = 0# H-bond acceptors = 5ClogP =4.15
Aspirin
Artemisinin
05/02/23
PURVI H. KAKRANI, SPSRC, VALASAN
4
Lipinski’s Rule of Fives …. Examples
Principles of Drug Design
MW = 429 Da# H-bond donors = 1# H-bond acceptors = 3ClogP = 4.74
MW = 407.5 Da# H-bond donors = 3# H-bond acceptors = 7ClogP = -0.17
RU-486 CCH3
O
OH
NCH3
CH3
C
NH
COOCH2CH3
CH2OCH2CH2NH2CH3
ClH3COOC
Amlodipine
05/02/23
PURVI H. KAKRANI, SPSRC, VALASAN
5
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
General Approaches
Principles of Drug Design
O
N
OH
H
OHCH3
HN
OH
CH3
HN
OH
CH3
HN
OH
CH3R
morphine morphinans benzomorphans 4-phenylpiperidines
05/02/23
PURVI H. KAKRANI, SPSRC, VALASAN
6
Chemical and Biochemical Isosteres
Principles of Drug Design
Grimm’s Hydride Displacement LawC N O F Ne
CH NH OH FH
CH2 NH2 OH2
CH3 NH3
Hinsberg’s Ring Equivalents
N
NNMe2
N
NNMe2
S
Tripelennamine Methaphenilene
Benzene, thiophene and pyridine are equivalent.e.g., H1-receptor antagonists … tripelennamine and methaphenilene
05/02/23
PURVI H. KAKRANI, SPSRC, VALASAN
7
Chemical and Biochemical Isosteres
Principles of Drug Design
Friedman’s Bioisosteres …. chemical and physical properties
N
N
OH
OH
N
N
OH
OH
FUracil ….. Fluorouracil (antineoplastic)
OH
COOH
OH
CONH2
Salicylic acid ….. Salicamide (analgesic)
OH
OH
CH3
OH
OH
Estradiol ….. Diethyl stilbestrol (estrogenic)
05/02/23
PURVI H. KAKRANI, SPSRC, VALASAN
8
Lengthening Alkyl Chains
Principles of Drug Design
1. Increase hydrophobicity, decrease water solubility2. Increase conformational flexibility3. May be directly involved in interaction with receptor
Bio
logi
cal A
ctiv
ity
Chain Length
‘Normal’ Behavior
O
N
OH
H
OHR
H
Morphine
R Activity
-CH3 Analgesic-CH2CH3 Agonist activity decreases-CH2CH2CH3 Antagonist activity increases-CH2CH2CH2CH3 Inactive (agonist + antagonist)-CH2CH2CH2CH2CH3 Antagonist activity increased-CH2CH2CH2CH2CH2CH3 Antagonist activity increased
05/02/23
PURVI H. KAKRANI, SPSRC, VALASAN
9
Flexibility of Drugs and Affinity
Principles of Drug Design
GCONF
G
Conf 1
Conf 2
RGCONF
G
Conf 1
Conf 2
R
= Bound Water= Free Water
GOBS = GComplex + GSolv + GConf = -RT ln K
05/02/23
PURVI H. KAKRANI, SPSRC, VALASAN
10
Dopamine Receptor Agonist
Principles of Drug Design
OHOH
NMe2
OHOH
NMe2
OHOH
NMe
OHOH
NMe
IV III II I = dopamine receptor agonist
II < III < IV < I
05/02/23
PURVI H. KAKRANI, SPSRC, VALASAN
11
Natural Products
~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
General
05/02/23
PURVI H. KAKRANI, SPSRC, VALASAN
12
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, ….
Natural Products General
05/02/23
PURVI H. KAKRANI, SPSRC, VALASAN
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• Evolution against challenges• Structural diversity• ‘Apparently’ unlimited quantity• Potency
Natural Products Advantages of Natural Products
Disadvantages of Natural Products
• Synthesis• Isolation• Identification
05/02/23
PURVI H. KAKRANI, SPSRC, VALASAN
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
05/02/23
PURVI H. KAKRANI, SPSRC, VALASAN
15
Natural Products
Selected Examples of Natural Product derived Drugs
CH3
CH3
OO
OH
H
H
HOOOHO
OH
H3C
H3C
OH H3C
OH
CH3
CH3
OO
OH
H
H
HOOOHO
OH
H3C
H3C
OH H3C
OH
OHDigitoxin
Digoxin
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
05/02/23
PURVI H. KAKRANI, SPSRC, VALASAN
16
Natural Products Selected Examples of Natural Product derived
Drugs
NN
HOH
OCH3
H N
N
OCH3
H
HOH
Quinidine Quinine
Quinidine …bark of Cinchona tree …… anti-arrhythmic drugQuinine … no cardiac activity … anti-infective … malaria
05/02/23
PURVI H. KAKRANI, SPSRC, VALASAN
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NH
NH H
HMeOOC
OCH3
O
OOCH3
OCH3OCH3
MeO
Reserpine
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 …
05/02/23
PURVI H. KAKRANI, SPSRC, VALASAN
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 ...
O
CH3
OOH
R
OCH3
R
CH3
OH
COO
CH3
OH
OH
OCH3
CH3
_
Mevastatin R1 = R2 = HLovastatin R1 = H; R2 = CH3Simvastain R1 = R2 = CH3
Pravastatin
05/02/23
PURVI H. KAKRANI, SPSRC, VALASAN
19
Natural Products Selected Examples of Natural Product derived
Drugs
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 …
O O
OH
CH3
O
O O
OH
OO
OH
*
Warfarin Dicoumarol
05/02/23
PURVI H. KAKRANI, SPSRC, VALASAN
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 …
O
OH
OH
O
COO
O
O
CH2OH
NHSO3
OHO
O
CH2OSO3
NHSO3
OHO
OH
OH
O
COOO
O
CH2OSO3
NHSO3
OHO
OSO3
OHO
COOO
O
CH2OSO3
NHCOCH3
OH
_
_
_
_
_
_
_
_ _
_
05/02/23
PURVI H. KAKRANI, SPSRC, VALASAN
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Natural Products Overview of Natural Products as Drugs Status in
the Period 1981-2002
0
100
200
300
400
500
V B NP NPD SNP S
V = vaccinesB = biologicalsNP = natural productsNPD = natural product derivativesSNP = synthetics derived from NPS = straight synthetics
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.
05/02/23
PURVI H. KAKRANI, SPSRC, VALASAN
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Natural Products Structural Comparison between Natural Products
and Combinatorial Compounds
Combinatorial Compounds
Natural Products
Drugs
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.
05/02/23
PURVI H. KAKRANI, SPSRC, VALASAN
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Natural Products Current Efforts
CH3
CH3
OHOH
H
CH3
H CH3
Trinervitane derivative
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
S
N
OO
CH3
O
OH
OH
Me
CH3
CH3
CH3
Me Me
Epothilone D
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)
05/02/23