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
ADME
• (Crystal structure)
• Stereochemistry

Absorbtion. Distribution, Metabolism, Excretion
(ADMET, ADMEtox)

KJM5230­H06
 Structure  ­  Mechanism of action

Acetylcholin 
(Neurotransmittor)
Acetylcholin Agonists
ca. 5Å

Carbacholin Nicotine Pilocarpine

O Me
O
N N N
O N O
H2N O H O N
N
H H
O

Protonated av phys. pH (pH≈7.4)
Det somatiske nervesystem Det autonome nervesystem

Det sympatiske Det parasympatiske
nervesystem nervesystem
Acetylcholin Antagonists
CNS CNS CNS
Atropin Cyclopentolat Tubocurarin
N H
N MeO
N
ganglion
Acetylkolin
OH Me
OH O O
Noradrenalin
O O HO
O
Synapse O
OH
Me
Reseptor
N
Effektor celle OMe
Me

KJM5230­H06
 Structure  ­  Mechanism of action
SAR: Structure Activity Relationships

Acetylcholine agonists: Small N­quartenary compds.
Acetylcholine antagonists: Larger N­quartenary compds.
O

N N

N N
N N
R
CO2Me NH2 N
O
O O
N R % Inhibition M. tuberculosis MIC 
O O H 6.25 μg/m L (μg/m L)
Cocaine
Procaine Lidocaine/Xylocaine
(1905) (1946)
-H 6
Acid labile ester
-CH 3 0

Hydrophilic Spacer -CH 2CH=CH 2 7

Lipophilic
Aminogroup ­Cn­X­
(Aryl)
(can be protonated) X: ­CO2­ -CH 2Ph >90 3.13
    ­CONH­
   ­NHCO­ 14
-SO 2Ph

-CH(CH 3)Ph >90 12.5

-Ph 13

-CH 2CH 2Ph 26

KJM5230­H06
Active compound identified Target identified
Target? Ligand?

KJM5230­H06
Structure  ­  Physiochemical properties

• Acid / base properties Human body: ca 75% water
• Water solubility pH blood ca 7.4 (physiolog. pH)
• Partition coefficient pH stomach 1 ­ 3.5
• (Crystal structure) pH duodenum ca. 4
• Stereochemistry pH urine ca. 6

Identification of acidic / basic functional groups
pKa determines degree of ionization different places in the body

KJM5230­H06
 Acetylcholin  Acetylcholin Antagonists Possible atropine analogs?
(Neurotransmittor)
ca. 5Å N
O N N N
OH
O OH OH OH
O O O O
O
N O O O
O
Cyclopentolat

H
O

N N
H
Cyclopentolate ­ tertiary amine, pKa ca. 10  O
OH  + H20 O
OH + H3O
O O

acid form baseform

[acid form] pH=pKa; [acid]= [base]
pKa = pH + log Henderson Hasselbach
pH<pKa; acid form dominates
[base form]
pH>pKa; basic form dominates
At pH 7.4

[acid form] [acid form] [acid form]

10 = 7.4 + log log = 2.6 = 398;    99.75% acid form
[base form] [base form] [base form]
= active form
N
H
OH
O

KJM5230­H06 O
Antibacterial sulfonamides

Old compound

At pH 6 (urine)

[acid form] [acid form] O Acid form ­ neutral

10.4 = 6 + log ≈ 25000 H2N S NH2 Low watersol. ­ crystals ­ 
[base form] [base form] O Kidney damage

Modern compound

O O
O O

N N N N

+
O O O O
-H

HN S Ar N S Ar N S Ar
N S Ar
At pH 6 (urine)
O
O O O

Sulfametoksasol [acid form]
≈ 1
base form, ionic, water sol. [base form]
pKa 6.1

N S Ar

KJM5230­H06
 Structure  ­  Physiochemical properties
• Acid / base properties
• Water solubility Ionisation     ­permanent charge
• Partition coefficient       ­acid / base properties
• (Crystal structure)
• Stereochemistry Hydrogen bonds

Ion ­ dipole bonds Intramoleculare interact. reduce water sol.
μ+
μ+
H H
O
μ -O μ+ O μ- H H
H H μ+ H
O
R N H
H CO2
R O Strong intramolecinteract.
R
Acidic form of amines Basic form of carboxylic acid NH3
(carboxylate)

O
H H

Salts between weak organic acids and weak organic bases does not dissolve well in water

KJM5230­H06
The more H­bonds possible ­ the more water sol.

H H
O O H H
H O
H

Alchohol O 3 H­Bonds H H
R H
Primary amine R N H O
3 H­Bonds
O H
H H
H H
O
H H
O O
H H

Aldehyde / ketone O 2 H­Bonds
R' H
R R' Secondary amine R N H O
2 H-Bonds
H

H H H H
O O O
H H
R'
Ester O 3 H­Bonds 1 H-Bonds
Secondary amine R N R''
R
R O
H H
H H O
O

KJM5230­H06
Prediction of water solubility ­ Empirical

Water solubilization of functional groups

Ex. monofuctional comp.
Functional group Monofunctional comp. Polyfunctional

comp. methanol ­ pentanol/hexanol 
are solubile
Alchohol 5 – 6 carbons 3 – 4 carbons

Phenol 6 – 7 3 – 4

Terbinafine
Antifungal agent
Ether 4 – 5 2

Aldehyde 4 – 5 2 N

Ketone 5 – 6 2

Amine 6 – 7 3
21 C­atom, tertiary amine solubilize 6 ­ 7 C atoms
Carboxylic acid 5 – 6 3
Insolubile (neutral form)
Ester 6 3
Corresponding acid (cationic) solubile
Amide 6 2 ­ 3

(solubile: >10 mg/mL)
Charge: 1 charge ­ 20­30 C
KJM5230­H06
 Water solubilization of functional groups

Functional group Monofunctional comp. Polyfunctional

comp.
Ex. polyfunctional comp.
Alchohol 5 – 6 carbons 3 – 4 carbons

Phenol 6 – 7 3 – 4 Betaxolol

Betablokker
Ether 4 – 5 2
Ether:     2
Aldehyde 4 – 5 2 O N
H Ether:      2
OH
Alchohol: 3­4
Ketone 5 – 6 2
Amine     2       
Amine 6 – 7 3 O
Tot:         9 ­ 10

Carboxylic acid 5 – 6 3 18 C­atomer (not solubile)

Ester 6 3

Amide 6 2 ­ 3

Charge: 1 charge ­ 20­30 C
KJM5230­H06
Structure  ­  Physiochemical properties
• Acid / base properties
• Water solubility
• Partition coefficient
• (Crystal structure)
logP P: Partition coefficient between n­octanol and water
• Stereochemistry
Experimental: MlogP or logPmeas

Fragment μ-val
ue
logP  Rt   (HPLC, TLC reverse phease)

C (aliph
atic +0.5
Phenyl +2.0 Calcd: ClogP
-Cl +0.5
p­value: hydrophilic ­ lipophilic value
-ONO2 +0.2 Betaxolol
Betablokker
-S- 0.0
12 x C aliphat:   +6.0
O=C-O- (carboxyl) -0.7
O N
H Ph:                      +2.0
O=C-N- (amide) -0.7 OH
3 x O:                   ­3.0
-O- (hydroxyl,ether) -1.0
N:                        ­1.0
N (am ine) -1.0 O
logP                     +4.0
-NO2 (aliphat.) -0.85
-NO2 (aromat.) -0.28 ClogP (SciFinder): 2.69
KJM5230­H06
 Absorbtion of Bioactive Compounds

Absorbtion from GI tract
Membrane

GI-tract
Blood
Stomach
pH 1-3
Often
rate limiting
Drug

Acidic /
Enzymatic break down
Duodenum
pH 5-7

+ digestive enzymes Binding to

biomolecules

Small Jejunum
intestine

Ileum
pH 7- 8

KJM5230­H06
Most drugs:   Passive diffusion

Lipophilic pKa pH
Membrane
Stomach Blood
pH 1 - 3 R-H R-H
Amount un ionized drug
R-CO2H R-CO2H

[acid form]
R-NH3 pKa = pH + log Henderson Hasselbach
[base form]

Low lipophilicity unionized form ­ low absorbtion
Water phase - extracellular fluid
logP ­ P: Partition coefficient between n­octanol and water 
Lipophilic phase - cell membrane

KJM5230­H06
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 ion­pair

KJM5230­H06
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

KJM5230­H06
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

Not too polar
ten (2 x 5) or fewer hydrogen-bond acceptors

molecular weight less than or equal to 500 Not too big

calculated logP less than or equal to 5

Not too hydrophobic

*Compound classes that are substrates for biological transporters

are exceptions to the rule.

KJM5230­H06
Structure  ­  Physiochemical properties
• Acid / base properties
• Water solubility
• Partition coefficient
• (Crystal structure)
• Stereochemistry

Biomolecules (reseptors, enzymes): Asymmetric
Enantiomers may behave differently:
•Absorbtion (membrane selectivity)
D A
•Metabolism
D •Binding to other reseptors than target
A C
C Drug   (loss, side effects)
B B •Binding to target reseptor

Biomolecular 
target

Desired responce KJM5230­H06
No desired resonce
Side effects??
Restricted rotation ­ optically active rotamers

P P

P P

(R)-(+)-BINAP (S)-(-)-BINAP

X-ray contrast agent

* CO2H
Chiral C-atom
O 4 stereoisomers
I I Chiral axis (restrict. tot.)
NH2
I

KJM5230­H06
•Screening/Design/Serendipity/Natural products  
•Lead compound
•Structure Optimisation Refinement of lead structure:
•Actual Drug •Determining pharmacophore
•Functional group modification

Pharmacophore: 
The part of the molecule that contains the functional groups that actually binds to the reseptor

Morfin Petidine Dextropropoxyphene

N
N N
OH
O
O
O O
OH O

KJM5230­H06
Antimycobacterials
Ar
Lead compound Rel high activity
N N
Y
O X N N

N Z
N
Cl N N

O R

N N
N N
N N
N N
R

R ≠ CH2Ph R=H, alkyl

Inactive

Pharmacophore??

Ar Ar
Azapurines?? Ar Ar
N N N
Deazapurines?? N
N R X
N N N
N
??
?? ??

KJM5230­H06
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

S
bp 81 oC bp 84 oC bp 116 oC

-CH=CH- and -S- are isosters -C= and -N= not isosters

(at least with respect to bp)

KJM5230­H06
Bioisosters:
Functional groups that results in approx. the same biological properties

Classical bioisosters
Steric and electronic similarities

Tetravalente
Monovalent Divalent
­F,  ­H ­C=S, ­C=O, ­C=NH, ­C=C­ N C

­OH, ­NH2
Rings
­H,  ­F, ­OH, ­NH2, ­CH3 Trivalente
­SH,  ­OH ­CH=, ­N=
­Cl,  ­Br, ­CF3  N S O

KJM5230­H06
 ­X μ μp % Inhib at MIC
O 6.25 μg/m L (μg/m L)
-H 0 0 >90 3.13
N N -F 0.15 0.06 >90 6.25
N -OH -0.61 -0.37 79 n.d.
N
-NH2 -1.23 -0.66 23 n.d.
-CH3 0.60 -0.17 >90 3.13
X Bioisosters

μ: electronic effects; μ>0 electron withdrawing, μ<0 electron donating

μ: Lipophilicity, μ>0 increasedlipophil. rel to H

Angiotensin II antagonists
(Hypertention)
Non­classical bioisosters
Not strong steric or  electronic similarities O N
N

N
N HO2C
NH
N

N N N N N
N N N
N N N N N
H H H H
N
pKa 14.2 pKa 10.3 pKa 9.2 pKa 4.9 ≈ karboksylsyrer
O
HO N
N

KJM5230­H06