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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
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:
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.
Why Do Drugs Look the Way they Do?
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.
Brill, May 2002
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
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
Brill, May 2002
Why Do Drugs Look the Way they Do?
How do Drugs get to their Targets!
Brill, May 2002
Brill, May 2002
Drugs can be administerd in many ways
They have to penetrate organ barriers and cell membranes to reach their target
Brill, May 2002
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
Brill, May 2002
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!
Brill, May 2002
• 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
Brill, May 2002
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
Brill, May 2002
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
Brill, May 2002
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?
Brill, May 2002
Daq + Raq DRaq + mH2O
aqaq
maq
RDOHDRRTGG
2ln
Drug-Target Interactions
aKRTGG ln
Brill, May 2002
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
+ +
Brill, May 2002
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
Brill, May 2002
Mostly hydrophobic interactions: Staurosporine binds CDK2
Noble, M. E. M. et al. Pharmacol. Ther. 82 (1999) 269-278
Brill, May 2002
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
Brill, May 2002
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!
Brill, May 2002
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
Brill, May 2002
•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)
Brill, May 2002
+
•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
Drug Target Selection
Only proteins with deep hydrophobic pockets are suitable for low MWt. Ligands...
Brill, May 2002
...such as proteins binding nucleotide cofactors
Brill, May 2002
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!
Brill, May 2002
Blume-Jensen, P. et al.Nature (London, U. K.) (2001) 411, 355-365
Various receptors with kinase-domainsintracellular
extracellular kinase domain
Brill, May 2002
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
Brill, May 2002
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
Brill, May 2002
•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
Brill, May 2002
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
Brill, May 2002
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.
AcknowledgementBrill, May 2002
Dr. Jean-Yves Trosset