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Why Do Drugs Look the Way they Do?
By Wolfgang K.-D. Brill
The 27th Summer School of Organic Synthesis at Gargnano, Italy 2002
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
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
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:
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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L. S. Goodman et al., Eds., Goodman and Gilman's The Pharmacological Basis of Therapeutics (McGraw-Hill, New York, ed. 9, 1996).
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DNA 2%Unknown 7%
Proteins 91%
Most Drugs Bind to ProteinsMost Drugs Bind to Proteins
Drug Target Selection
• 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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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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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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H-bonds ?
HOH........OH2 - 6.4 Kcal mol-1H2O........HSCH3 - 3.2 Kcal mol-1HOH........S(H)CH3 - 3.1 Kcal mol-1Imidazolinium/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
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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
Drug Target Selection
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
+ kinaseMg2+
+
Kinase mechanism
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Hydrophobic pockets within ATP-binding domains
Traxler, P. et. al. Pharmacol. Ther. 82 (1999) 195-206
Why Do Drugs Look the Way they Do?
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
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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?
Why Do Drugs Look the Way they Do?
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.
Why Do Drugs Look the Way they Do?
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.