Drug Design:
Functional groups / Pharmacological Activity
Structure - Mechanism of action
(Interaction with target)
Structure - Physiochemical properties (Bioavailability etc)
•
•
•
•
•
Acid / base properties
Water solubility
Partition coefficient
(Crystal structure)
Stereochemistry
ADME
Absorbtion. Distribution, Metabolism, Excretion
(ADMET, ADMEtox)
KJM5230-H06
Structure - Mechanism of action
Acetylcholin
(Neurotransmittor)
ca. 5Å
Acetylcholin Agonists
O
O
Pilocarpine
Nicotine
Carbacholin
Me
N
O
N
H2N
N
N
O
O
H
N
O
H
O
N
H
Protonated av phys. pH (pH- 7.4)
Det somatiske nerves ystem
Det autonome nervesys tem
CNS
Det sympatiske Det paras ympatis ke
nervesystem
nervesystem
CNS
CNS
Acetylcholin Antagonists
Atropin
N
N
H
MeO
ganglion
N
OH
Acetylkolin
Noradrenalin
Tubocurarin
Cyclopentolat
OH
O
Me
O
O
O
HO
O
Synapse
O
OH
Me
Reseptor
Effektor celle
N
Me
KJM5230-H06
OMe
Structure - Mechanism of action
SAR: Structure Activity Relationships
Acetylcholine agonists: Small N-quartenary compds.
Acetylcholine antagonists: Larger N-quartenary compds.
O
N
N
N
N
N
CO2Me
NH2
O
Cocaine
O
O
N
O
R
N
H
O
Procaine
(1905)
N
R
Lidocaine/Xylocaine
(1946)
% Inhibition M. tuberculosis
6.25 g/mL
-H
6
-CH3
0
-CH2CH=CH2
7
MIC
(g/mL)
Acid labile ester
Hydrophilic
Aminogroup
(can be protonated)
Spacer
-Cn-XX: -CO2-CONH-NHCO-
Lipophilic
(Aryl)
-CH2Ph
>90
-SO2Ph
14
-CH(CH3)Ph
KJM5230-H06
>90
-Ph
13
-CH2CH2Ph
26
3.13
12.5
Active compound identified
Target?
Target identified
Ligand?
KJM5230-H06
Structure - Physiochemical properties
•
Acid / base properties
•
•
•
•
Water solubility
Partition coefficient
(Crystal structure)
Stereochemistry
Human body: ca 75% water
pH blood ca 7.4 (physiolog. pH)
pH stomach 1 - 3.5
pH duodenum ca. 4
pH urine ca. 6
Identification of acidic / basic functional groups
pKa determines degree of ionization different places in the body
KJM5230-H06
Acetylcholin
(Neurotransmittor)
Possible atropine analogs?
Acetylcholin Antagonists
ca. 5Å
N
N
N
O
OH
O
O
O
O
O
OH
OH
OH
O
O
N
N
O
O
O
O
Cyclopentolat
H
Cyclopentolate - tertiary amine, pKa ca. 10
pKa = pH + log
[acid form]
Henderson Hasselbach
[base form]
H
N
N
OH
O
+ H3O
OH
+ H20
O
O
O
acid form
baseform
pH=pKa; [acid]= [base]
pH<pKa; acid form dominates
pH>pKa; basic form dominates
At pH 7.4
10 = 7.4 + log
[acid form]
[base form]
log
[acid form]
= 2.6
[base form]
[acid form]
= 398; 99.75% acid form
[base form]
H
N
= active form
OH
KJM5230-H06
O
O
Antibacterial sulfonamides
Old compound
At pH 6 (urine)
10.4 = 6 + log
[acid form]
[acid form]
[base form]
[base form]
O
H2N S
O
- 25000
NH2
Acid form - neutral
Low watersol. - crystals Kidney damage
Modern compound
O
N
O
O
- H+
HN S Ar
O
Sulfametoksasol
pKa 6.1
N
O
N S Ar
O
O
O
N
N
O
N S Ar
O
O
N S Ar
O
At pH 6 (urine)
[acid form]
O
N
base form, ionic, water sol.
O
N S Ar
O
KJM5230-H06
[base form]
- 1
Structure - Physiochemical properties
Ion - dipole bonds
•
Acid / base properties
•
Water solubility
Ionisation
•
•
•
Partition coefficient
(Crystal structure)
Stereochemistry
Hydrogen bonds
+
+
H
H
+ O H
+
Acidic form of amines
H
O
H
O
R N H
H
Intramoleculare interact. reduce water sol.
H
H
- O
-permanent charge
-acid / base properties
R
CO2
O
Strong intramolec interact.
R
Basic form of carboxylic acid
(carboxylate)
NH3
H
O
H
Salts between weak organic acids and weak organic bases does not dissolve well in water
KJM5230-H06
The more H-bonds possible - the more water sol.
H
H
O
O
H
Alchohol
H
R
O
H
H
H
3 H-Bonds
H
O
H
O
H
Primary amine
R
H
H
O
H
H
3 H-Bonds
O
H
2 H-Bonds
O
R
O
H
H
O
Aldehyde / ketone
H
N H
R'
Secondary amine
R'
R
H
N H
O
2 H-Bonds
H
H
H
O
O
H
H
Ester
3 H-Bonds
O
R
H
O
H
R'
Secondary amine
R
1 H-Bonds
N R''
R
H
H
O
O
H
KJM5230-H06
O
H
Prediction of water solubility - Empirical
Water solubilization of functional groups
Functional group Monofunctional comp. Polyfunctional
comp.
Alchohol
5 – 6 carbons
3 – 4 carbons
Phenol
6–7
3–4
Ether
4–5
2
Aldehyde
4–5
2
Ketone
5–6
2
Amin e
6–7
3
Carboxyli c acid
5–6
3
Ex. monofuctional comp.
methanol - pentanol/hexanol
are solubile
Terbinafine
Antifungal agent
N
21 C-atom, tertiary amine solubilize 6 - 7 C atoms
Insolubile (neutral form)
Ester
6
3
Amid e
6
2-3
Charge: 1 charge - 20-30 C
Corresponding acid (cationic) solubile
(solubile: >10 mg/mL)
KJM5230-H06
Water solubilization of functional groups
Functional group Monofunctional comp. Polyfunctional
comp.
Alchohol
5 – 6 carbons
3 – 4 carbons
Phenol
6–7
3–4
Ether
4–5
2
Aldehyde
4–5
2
Ex. polyfunctional comp.
Betaxolol
Betablokker
O
OH
2
Ether:
2
Alchohol: 3-4
Ketone
5–6
Amin e
6–7
3
Carboxyli c acid
5–6
3
Ester
6
3
Amid e
6
2-3
Charge: 1 charge - 20-30 C
N
H
Ether:
2
Amine
2
Tot:
9 - 10
O
18 C-atomer
KJM5230-H06
(not solubile)
Structure - Physiochemical properties
•
•
Acid / base properties
Water solubility
•
Partition coefficient
•
•
(Crystal structure)
Stereochemistry
logP
P: Partition coefficient between n-octanol and water
Experimental: MlogP or logPmeas
Fragment
-value
C (aliph atic
+0.5
Phenyl
+2.0
-Cl
+0.5
-ONO2
+0.2
-S-
0.0
O=C-O- (carboxyl)
-0.7
O=C-N- (amide)
-0.7
logP  Rt (HPLC, TLC reverse phease)
Calcd: ClogP
-value: hydrophilic - lipophilic value
Betaxolol
Betablokker
12 x C aliphat: +6.0
O
OH
-O- (hydroxyl, ether) -1.0
N (amine )
-1.0
-NO2 (aliph at.)
-0.85
-NO2 (aromat.)
-0.28
N
H
Ph:
+2.0
3 x O:
-3.0
N:
-1.0
logP
+4.0
O
KJM5230-H06
ClogP (SciFinder): 2.69
Absorbtion of Bioactive Compounds
Absorbtion from GI tract
Membrane
GI-tract
Blood
Stomach
pH 1-3
Drug
Often
rate limiting
Acidic /
Enzymatic break down
Duodenum
pH 5-7
+
Binding to
biomolecules
digestive enzymes
Small
intestine
Jejunum
Ileum
pH 7- 8
KJM5230-H06
Most drugs: Passive diffusion
Stomach
pH 1 - 3
Lipophilic
Membrane
R-H
R-CO2H
R-NH3
pKa
pH
Blood
R-H
Amount un ionized drug
R-CO2H
pKa = pH + log
[acid form]
Henderson Hasselbach
[base form]
Low lipophilicity unionized form - low absorbtion
Water phase - extracellular fluid
logP - P: Partition coefficient between n-octanol and water
KJM5230-H06
Lipophilic phase - cell membrane
Crossing the membrane
Passive transport / diffusion
High conc.
Chanel protein
Low conc.
Rate  Conc. absortion site (1. order kinetics)
% Drug absorbed  lipophilicity
Size of molecule
Certain ionic compounds may go thru as ion-pair
KJM5230-H06
Active transport / Carrier mediated transport
•Less common
•Structural recemblanse with for instance nutritional compound
•Transport against conc. gradient
•Mechanism saturated at high conc.
•Competition for carrier molecules, compounds with structural resemblance
Energy
KJM5230-H06
The Lipinski "Rule of Five"
states that compounds are likely to have good absorption and permeation
in biological systems and are more likely to be successful drug candidates
if they meet the following criteria:
five or fewer hydrogen-bond donors
ten (2 x 5) or fewer hydrogen-bond acceptors
molecular weight less than or equal to 500
calculated logP less than or equal to 5
Not too polar
Not too big
Not too hydrophobic
*Compound classes that are substrates for biological transporters
are exceptions to the rule.
KJM5230-H06
Structure - Physiochemical properties
•
•
•
•
Acid / base properties
Water solubility
Partition coefficient
(Crystal structure)
•
Stereochemistry
Biomolecules (reseptors, enzymes): Asymmetric
A
D
A
Enantiomers may behave differently:
•Absorbtion (membrane selectivity)
C
Drug
•Metabolism
•Binding to other reseptors than target
D
C
B
B
Biomolecular
target
Desired responce
No desired resonce
Side effects??
(loss, side effects)
•Binding to target reseptor
Restricted rotation - optically active rotamers
P
P
P
P
(S)-(-)-BINAP
(R)-(+)-BINAP
X-ray contrast agent
* CO2H
Chiral C-atom
O
I
I
Chiral axis (restrict. tot.)
NH2
I
KJM5230-H06
4 stereoisomers
•Screening/Design/Serendipity/Natural products
•Lead compound
•Structure Optimisation
Refinement of lead structure:
•Determining pharmacophore
•Functional group modification
•Actual Drug
Pharmacophore:
The part of the molecule that contains the functional groups that actually binds to the reseptor
Morfin
Petidine
N
OH
O
Dextropropoxyphene
N
N
O
O
OH
O
O
KJM5230-H06
Antimycobacterials
Ar
Lead compound
O
N
Z
N
N
Cl
Y
N
X
N
Rel high activity
N
N
N
O
R
N
N
N
N
N
N
N
N
R
R ° CH2Ph
R=H, alkyl
Inactive
Pharmacophore??
Ar
Azapurines??
N
N
Deazapurines??
N
N
Ar
Ar
Ar
N
N
N
??
KJM5230-H06
N
R
X
N
??
??
Improvement of lead by functional group modification
•Activity
•Toxicity
•Bioavailability
•Metabolism
Isosters:
Functional groups that results in approx. the same properties
Steric and electronic similarities
N
S
bp 81
oC
bp 84
bp 116 oC
oC
-CH=CH- and -S- are isosters
-C= and -N= not isosters
(at least with respect to bp)
KJM5230-H06
Bioisosters:
Functional groups that results in approx. the same biological properties
Classical bioisosters
Steric and electronic similarities
Tetravalente
Monovalent
-F, -H
-OH, -NH2
-H, -F, -OH, -NH2, -CH3
-SH, -OH
-Cl, -Br, -CF3
Divalent
-C=S, -C=O, -C=NH, -C=C-
Trivalente
-CH=, -N=
N
Rings
N
KJM5230-H06
C
S
O
-X

p
-H
-F
-OH
-NH2
-CH3
Bioisosters
0
0.15
-0.61
-1.23
0.60
0
0.06
-0.37
-0.66
-0.17
O
N
N
N
N
X
% Inhib at
6.25 g/mL
>90
>90
79
23
>90
MIC
(g/mL)
3.13
6.25
n.d.
n.d.
3.13
: electronic effects; >0 electron w it hdrawing, <0 electron dona ting
: Lipophili city, >0 incr eased li pophil . rel t o H
Angiotensin II antagonists
(Hypertention)
Non-classical bioisosters
Not strong steric or electronic similarities
O
N
N
N
N
N
N
H
pKa 14.2
N
N
H
N
pKa 10.3
N
H
N
N
pKa 9.2
N
NH
N N
N
N
H
HO2C
N
N
pKa 4.9 - karboksylsyrer
O
HO
N
KJM5230-H06
N