Why Do Drugs Look The Way They Do

Why Do Drugs Look the Way they Do?

By Wolfgang K.-D. Brill

Brill, May 2002

The Blockbusters in 2000

MeO NH

NS

O

N

OMe

Prilosec

NH

NS

O

N

OCF3

Prevacid

F

N

PhNHO

Ph

i-PrOHOH

HO2C

Lipidor

O

O OH

HO

O

Zocor

NH

O

CF3Ph

Prozac

SOO

NNNH2

Celebrex

ClCl

NH

Zoloft

N

NH S

N

N

Zyprexa

AAAAAAS APPRLICDSR VLERYLLEAK EAENITTGCA EHCSLNENIT VPDTKVNFYA AAAAAAAAAA AAAAAAAAAA AAAAAAAASA AAS WKRMEVGQQA VEVWQGLALL SEAVLRGQAL LVNSSQPWEP LQLHVDKAVS GLRSLTTLLR ALGAQKEAIS PPDAASAAPL RTITADTFRK LFRVYSNFLR GKLKLYTGEA CRTGD AAAAAAAAAA S

Epogen, Procrit:

Brill, May 2002

Blockbusters 2000: Mostly Heterocycles

MeO NH

NS

O

N

OMe

Prilosec

NH

NS

O

N

OCF3

Prevacid

F

N

PhNHO

Ph

i-PrOHOH

HO2C

Lipidor

O

O OH

HO

O

Zocor

NH

O

CF3Ph

Prozac

SOO

NNNH2

Celebrex

ClCl

NH

Zoloft

N

NH S

N

N

Zyprexa


Epogen, Procrit:

Brill, May 2002

The Blockbusters 2000: Mostly Small Molecules

MeO NH

NS

O

N

OMe

Prilosec

NH

NS

O

N

OCF3

Prevacid

F

N

PhNHO

Ph

i-PrOHOH

HO2C

Lipidor

O

O OH

HO

O

Zocor

NH

O

CF3Ph

Prozac

SOO

NNNH2

Celebrex

ClCl

NH

Zoloft

N

NH S

N

N

Zyprexa


Epogen, Procrit:

Brill, May 2002

X

R

R

Various functional groups

HHydrophobic

residues

C

- electron clouds

H

Polar residues

Cyclic molecules provide the highest density of atoms per surface, heterocycles the highest density of chemical functionalities with

well-defined orientation in space per surface.


Lets look at the Targets!

Brill, May 2002

Drug Target Selection

• Genomics helps to identify “disease genes” Disease genes are genes whose products are directly or indirectly responsible for a disease

• When products of a “disease gene” are not suitable

targets other proteins linked via physiological or pathophysiological pathways may be.

• About 5000-10000 targets my be suitable for drug intervention

Drews, J. Science (Washington, D. C.) 287 (2000) 1960-1963.

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Brill, May 2002

L. S. Goodman et al., Eds., Goodman and Gilman's The Pharmacological Basis of Therapeutics (McGraw-Hill, New York, ed. 9, 1996).

Brill, May 2002

DNA 2%Unknown 7%

Proteins 91%

Most Drugs Bind to ProteinsMost Drugs Bind to Proteins


• Biological relevance (often the only factor considered but can be difficult to estimate without a drug)

• Kinetics for the endogenous process

• Selectivity of action

• The structure of the drug target and its suitability for interaction with low M. Wt. ligands

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How do Drugs get to their Targets!

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Drugs can be administerd in many ways

They have to penetrate organ barriers and cell membranes to reach their target

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Since many targets are intracellular, cellular membranes present a severe obstacle

1 outside the cell 2 inside the cell3 freeze fracture passes through the middle bilayer protein 4,5,7,8, 9 integral membrane proteins6,11 peripheral membrane proteins10 carbohydrate residuesSinger, S. J.; Nicolson, G. L. Science (Washington, D. C.) 175 (1972) 723

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Passive diffusionrule of 5 obligatory

Active transportdrugs use systems for:amino acidsL-DOPA basic polypeptides amino glycosides

Receptor mediated transport1,2: binding to receptor3: adaptin addition4: accumulation of receptors5: formation of vesicle6-8: formation of endosome and recycling of receptor9: intracellular distribution via endosome

vesicular transport

out outin

Lüllmann, H.; Mohr, K.; Ziegler, A. Taschenatlas der Pharmakologie, 3rd ed. Georg Thieme Verlag Stuttgart, New York 1996

Transport of drugs

Statistical analysis of drugs, which are orally available revealed similarities of in

physicochemical properties!

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• Number of H-bond donors (NH and OH): 0 - 5• Number of H-acceptors (N: and O:): 5 - 10• LogP: -2 - 5• Molecular weight: 200 - 500• No of rotatable bonds:• Formal charge: -2 - 2• Number of non-hydrogens: 20 - 50• Polar surface area: < 99original Lipinski rule or rule-of-5

Distribution of “rule-of-5 properties” among drugs in phase II development

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NH, OH N:, O: C logP MW

0%10%20%30%40%50%60%70%80%90%

100%

not conformrule-of-5

Lipinski C. A. et al. Adv. Drug Delivery Rev. 23 (1997) 3-25

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Calculation of the polar surface area and correlation with bioavailability

Bioavailability type: r2 (TPSA)

Oral drug absorption: 0.91Caco-2-permeabilty: 0.56-0.96Blood brain barrier: 0.66-0.84Human jejunumpermeability: 0.75

Ertl et al. J. Med. Chem. 43 (2000) 3714-3717

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All compoundsRule-of-5

compounds

Drugs

Bioavailability imposes stringent restrictions upon the chemical and physical properties of drugs

How can the drug-like compounds interact with proteins?

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Daq + Raq DRaq + mH2O

aqaq

maq

RDOHDRRTGG

2ln

Drug-Target Interactions

aKRTGG ln

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H-bonds ?

HOH........OH2 - 6.4 Kcal mol-1

H2O........HSCH3 - 3.2 Kcal mol-1

HOH........S(H)CH3 - 3.1 Kcal mol-1

Imidazolinium/water - 14.0 Kcal mol-1CH3CO2

- .......HOH - 19.0 Kcal mol-1

Sint

HDWSrt

Svib

HDR

RW

SW

+ +

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H-bonds cannot lead to high binding constants because:

• Drugs are solvated prior to entering the target• The water binding to the drug has to be replaced by the target• The hydrogen bond on the target has to be significantly stronger than that of the drug with water• In order to obtain high binding many H-bonds are necessary• A compound with that many H-bonds is too polar for

passive uptake

Brill, May 2002

Hydrophobic interactions?

drug poorly solvated by

water

alignment with target surfacewater does not bind

well to target site:can readily be

displaced

Brill, May 2002Mostly Hydrophobic Interactions: ATP complements its binding site in CDK2

Eksterowicz, John E. et al. J. Mol. Graphics & Modelling 20 (2002) 469-477.

Example for hydrophobic interactions in nature:Brill, May 2002

Multiple -stacking of aromatics in a telomerase complex

Horvath, M. P. et al. Cell 95 (1998) 963-974

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Mostly hydrophobic interactions: Staurosporine binds CDK2

Noble, M. E. M. et al. Pharmacol. Ther. 82 (1999) 269-278

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DOF -0.7 -0.7- -1.0C(sp2) 0.7 0.6- 0.8C(sp3) 0.8 0.1- 1.0N+ 11.5 11.4- 15.0N 1.2 0.8- 1.8CO2

- 8.2 7.3- 10.3OPO3

- 10.0 7.7- 10.6OH 2.5 2.5- 4.0C=O 3.4 3.2- 4.0O,S 1.1 0.7- 2.0 halogen 1.3 0.2- 2.0

Group Energy range over (Kcalmol-1) 200 cpds.

DOF: degrees of freedom

Contributions of functional groups to binding

Andrews, P. R. et al. J. Med. Chem. 27 (1984) 1648-1657

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X

R

R

Fixation of functional groups in space

HAlignment with target

surface

C

- Interactions

H

H-bond

The greater the surface of a drug involved in interactions with its target, the greater the binding!

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The interactions of a kinase inhibitor with the interior of a binding pocket

Gray, N. S. et al. Science (Washington, D. C.) 281 (1998) 533-538

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•Large drug molecule•Difficult to synthesize•Poor passive uptake•Hydrophilic (for solubility)

+

•Flat, hydrophillic protein surface

Only large molecules can bind to shallow surface !

•Small drug molecule•Easy to synthesize•bioavailable

+

Protein surface•Poorly hydrated•Stressed due to hydrophobic collaps

Small molecule can bind to deep fold!

How drugs bind to proteins

•Large drug molecule•Difficult to synthesize•Poor passive uptake•Hydrophilic (for solubility)

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+

•Flat, hydrophillic protein surface

Only large molecules can bind to shallow surface !

•Small drug molecule•Easy to synthesize•bioavailable

+

Protein surface•Poorly hydrated•Stressed due to hydrophobic collaps

Small molecule can bind to deep fold!

How drugs bind to proteins

Brill, May 2002

All proteins

Proteins with deep hydrophobic

pockets

Proteins binding to rule-of-5 compounds

All compoundsRule-of 5

compounds

Targets

Drugs


Only proteins with deep hydrophobic pockets are suitable for low MWt. Ligands...

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...such as proteins binding nucleotide cofactors

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One type of protein requiring the nucleotide cofactor

ATPare protein tyrosine kinases

They are• involved in the regulation of cellular processes via substrate phosphorylation• Dysfunction of those processes lead to many diseases such as

cancer• Cofactors can readily diffuse in and out of binding sites!• Binding sites are not optimized toward very tight binding:

competitive inhibition possible!• There are many different binding pockets for cofactors:

selective binding possible!

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Blume-Jensen, P. et al.Nature (London, U. K.) (2001) 411, 355-365

Various receptors with kinase-domainsintracellular

extracellular kinase domain

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OOPO

OO P

O

OP OO O

OHOH

N

NN

NO

NH2OH

Protein

OOPO

OP OO O

OHOH

N

NN

NO

NH2O

OPO

O

Protein

+kinase

Mg2+

+

Kinase mechanism

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Hydrophobic pockets within ATP-binding domains

Traxler, P. et. al. Pharmacol. Ther. 82 (1999) 195-206


Heterocycles provide opportunities for designing functional group isosteres

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•Improve bioavailability•Improve activity•Reduce side effects•Reduce toxicity•Circumvent patents•Design new chemical entities

Brill, May 2002

N

OH NH

OHOH N

NH

Y

OOH N

OOH

N

OH

Y: OY: NH

Bioisosteres for phenyl and phenol residues• To improve solubility • To reduce toxicity

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OH

O

NN

NNH

NO

NHO

NHN

O

O

R

YN R

O

OO

N

O

R

OR' Y

NN

R

YN

R

YN

OR

YNN

O R NN

NY

RO

R

NH

NYOR

N

NOOR

N

NYOH

NO

O

OR

NH2

O

ON

N

NNH

N

NN

O

N

NH

NO

Y: OY: S

Y: OY: S

Y: OY: S

Y: OY: S

Y: OY: CH2Y: NHY: NR'

Y: OY: S

Y: OY: S

Y: CHY: N

Bioisosters for carboxylic acid derivatives

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Why are many drugs aromatics?

Comparison of two compounds C8H8:

Which has the greater surface?


Brill, May 2002

• Drugs are small molecules with some hydrophobicity to be bioavailable.• Small molecules can only bind to proteins with deep hydrophobic pockets or folds.• To bind to such folds a drug must complement the inner surface of the hydrophobic pocket or fold.• This requires the highest possible density of functionality per drug surface preoriented in space. • This can best be achieved with heterocycles being aromatic or with heterocycles in conjunction with other aromatic systems.• Heterocycles provide many facile and rapid ways for derivatizations.

AcknowledgementBrill, May 2002

Dr. Jean-Yves Trosset

Why Do Drugs Look The Way They Do

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