what crystal structure databases tell us about...
TRANSCRIPT
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What Crystal Structure Databases Tell us about Conformations of Drug-like Molecules
Martin Stahl, Roche Basel, June 2008
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bioactiveconformation
ΔG = 0.5 kcal/mol → factor 2.3 affinity reductionΔG = 1.0 kcal/mol → factor 5.4 affinity reductionΔG = 2.0 kcal/mol → factor 30 affinity reductionΔG = 3.0 kcal/mol → factor 160 affinity reduction
ΔG
Conformational Energies MatterStrained Bioactive Conformations Affect Binding Energy
global minimumIn solution
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Required GeneralizationsStatistics over Recurring Fragments
ON
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1600
1700
1800Prous CSD PDB
0>10 10-8 7-5 4-3 2 1
Frequency of Core Occurrence in Prous
100
200
300
400
500
Num
ber o
f Dru
g C
ores
Coverage of Relevant SubstructuresIn Crystal Structure Databases
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Cis or Trans? From Amides to Electrostatic Repulsion
Generalized Allylic Strain
The Sulfonyl Group
Properties of Aniline Derivatives
Project Example: New F.VIIa Inhibitors
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0
500
1000
1500
2000
2500
0 30 60 90 120 150
Amides Planar Systems with trans Configuration
NH
O
Torsion angle (deg.)
freq
uenc
y
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Novobiocin – Gyrase complexA peptide inhibitor of HIV protease
1aj6
1htg
In both cases the cis amide conformation allows the formation of significant lipophilic contacts.
Examples of Cis Amide BondsProtein-Ligand Complexes
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VIGXOY
The alternative cis-trans conformationis completely planar and allows the formationof planar H-bonding networks.
CIHCUR
“normal” case: Note deviation from planarity
DUVHOR10
Examples of Cis Amide BondsImides
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1ybhNICGAH
Acylated AminopyrimidinesCis Amide Conformations in the Absence of H-Bonds
N
NH
O N
NH
O
N
N
NH
O
N
N
NH
O
but:
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0
20
40
60
80
100
0 30 60 90 120 150
NX
X
OH
N
O
N
O
Electrostatic Repulsion Determines EquilibriaAlkoxypyridines
Lys33
Inhibitor NU6102with monomeric CDK2 (2c6t, green) and in CDK2/cyclin A complex (2c6m, cyan).
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0
10
20
30
0 30 60 90 120 150
NH
O
H
H
NO
N
O
Electrostatic Repulsion Determines EquilibriaBenzylic ortho Substituents at Pyridines
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Cis or Trans? From Amides to Electrostatic Repulsion
Generalized Allylic Strain
The Sulfonyl Group
Properties of Aniline Derivatives
Project Example: New F.VIIa Inhibitors
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0
10
20
0 20 40 60 80 100 120 140 160
H
HH
H
YUVDEY
ZIZCOA
syn skew
For 1-butene, the skewconformation is favored by ~0.2 kcal/mol over syn(gas phase).
Preferred Conformations of Allylic SystemsEnergy Minima at 120° to Double Bond
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H
H
H
= 0 > 4 kcal/mol ~3.4 kcal/mol
Preferred Conformations of Allylic SystemsAllylic 1,3-Strain: Syn-Rotamer Strongly Avoided
0
10
20
30
40
0 30 60 90 120 150
[C,H]
HH
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HH
H
H
HH
syn skew
Preferred Conformations of Allylic SystemsAllylic 1,2-Strain: Syn-Rotamer Preferred
0
5
10
15
20
25
0 30 60 90 120 150
H
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τ = 110˚
τ = 0˚
MYCPHA1jr1 (IMPDH Complex Structure)
Allylic Strain in ActionThe Example of Mycophenolic Acid
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O
O OH
O
O
OH
O
O OH
O
O
OH
O
O OH
O
O
OH
0
10
20
30
0 60 120 1800
10
20
30
0 60 120 1800 60 120 180
0
50
100
0 60 120 1800
50
100
0 60 120 1800 60 120 180
0
200
400
600
0 60 120 1800
200
400
600
0 60 120 1800 60 120 180
3 0.02 μM
Bioactive conformation
2 0.14 μM
1 1.0 μM
Freq
uenc
y
Mycophenolic Acid AnalogsTorsion Histograms of Alternative Linkers
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0
10
20
30
0 20 40 60 80 100 120 140 160
O
NH
O
N
N
O
0
10
20
30
40
0 20 40 60 80 100 120 140 160
O
NH
H
H~
~
Translating Allylic 1,3-Strain to Related SystemsAmide Analogies
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ZOWWEN CAGDUKZOHNUF
Tertiary AmidesSubstituents Point out of Plane
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BOAYPI
Acylated PiperidinesEnforcement of Axial Substituents
REYPUG
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Acylated Piperidines and Related StructuresPDB Examples
MQPA – thrombin complex (1etr) DPPIV complex, J. Med. Chem. 2008, 51, 589–602
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FKBP12 complex structure (1j4i)
Acylated PiperidinesAnalogous Effects with Sulfonamides
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Cis or Trans? From Amides to Electrostatic Repulsion
Generalized Allylic Strain
The Sulfonyl Compounds
Properties of Aniline Derivatives
Project Example: New F.VIIa Inhibitors
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Sulfonamides are not Amide Isosteres!
FIBKUWPABZAM
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SO O
N SO O
C
GESSUS
Preferred Conformations of Sulfonamidesp Orbitals and Lone Pairs Bisect the O=S=O Angle
0
10
20
30
40
50
60
0 30 60 90 120 1500
100
200
300
400
500
600
700
800
900
S[C,N]
OOH
H
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BULFOD
0
100
200
300
400
500
600
700
800
900
0 30 60 90 120 1500
5
10
15
20
25
30
S[C,N]
OOH
[not H]
Aryl-Sulfonyl CompoundsOrtho Substituents Shift the Torsion Angle Distribution
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PKA fivefold mutant model of Rho-Kinase complexed with fasudil (2gni, left) andan analog (2gnh, right).
Aryl-Sulfonyl CompoundsExtreme Cases of ortho Substitution
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S0 20 40 60 80 100 120 140 160 180
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
d N
-pla
ne (Å
)
τ CSNC (deg.)
SO O
NSO O
N
Alternate Sulfonamide ConformationsNitrogen Hybridization and Inversion
KATLEW
ADISAH
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HPTZDXVOGKILHHBPTH
WABYIH HITQOQ CADTOQ
Aryl-Sulfonyl CompoundsPreferred S-N Torsion leads to Axial N Substituents
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Farnelyltransferase complex (1sa5) Stromelysin complex (1ciz)
Sulfonamide Special EffectsLonger Bond Distances Allow Folding Back
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Cis or Trans? From Amides to Electrostatic Repulsion
Generalized Allylic Strain
The Sulfonyl Compounds
Properties of Aniline Derivatives
Project Example: New F.VIIa Inhibitors
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0
5
10
15
20
25
30
35
40
45
0 30 60 90 120 1500
5
10
15
20
25
30
35
40
Aryl Rings - Aniline DerivativesInterplay between N Hybridization and Rotation
N
H
H
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PDABZA01
MPABZA01
LIYSIV
3.10 Å
GILYOP
0.37 Å
electron withdrawingsubstituents decreasepyramidalization
0.22 Å
fully planar
fully planar
electron pushingsubstituents increasepyramidalization.
environment plays an important role.
Aniline DerivativesVaryin Degrees of Pyramidalization
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LOSQEP
NAXDAR
Cyclic Aniline DerivativesPyramidalization Strongly Affects Molecular Shape
DUBXAZICOKOA
ZUHRID01
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Benzamides and Acylated AnilinesPlanar or Nonplanar?
ONHNH O
0
5
10
15
20
25
30
35
0 30 60 90 120 1500
10
20
30
40
50
60
70
0
10
20
30
40
50
60
70
80
90
0 30 60 90 120 1500
10
20
30
40
50
60
70
80
90
100
τ
Local energy maximum at 0°, but PDB structures mostly planar
Global energy minimum at 0°, PDB structures mostly planar
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Cis or Trans? From Amides to Electrostatic Repulsion
Generalized Allylic Strain
The Sulfonyl Group
Properties of Aniline Derivatives
Project Example: New F.VIIa Inhibitors
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NH2 NH
NH
O
NH
O
NH
0.12 μM
NH2 NH
NH
O
inactive!
New F.VIIa InhibitorsDesign of a New Scaffold, First Iteration
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NH
O
0
5
10
0 30 60 90 120 150 180
C(sp2)NH
O
0
5
10
0 30 60 90 120 150 180
New F.VIIa InhibitorsConformations of Cabon and Oxygen Derivatives
C(sp2)NH
O
O
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NH2 NH
NH
OO
NH2 NH
NH
OO
inactive 11 μM
New F.VIIa InhibitorsDesign of a New Scaffold, Second Iteration
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NH2 NH
NH
OO
FO
1.7 μM
New F.VIIa InhibitorsConfirmed Binding Mode of Mandelic Acids
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Alkoxymethyl Amides – The General CaseSecondary Amides: Syn - Tertiary Amides: Trans
0
20
40
60
80
100
120
0 30 60 90 120 1500
10
20
30
40
50
60
70
80
90
0
10
20
0 30 60 90 120 150
NH
O
ON
OO
H H
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HCV polymerase palm site complex (2qe5) locked: 11bHSD-1 complex (2irw)
Alkoxymethyl AmidesPDB Examples
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Acknowledgments
• Scientists worldwide contributing to CSD and PDB
• Ken Brameld, Deborah Reuter, Roche Palo Alto
• Bernd Kuhn, Roche Basel
• Prof. Klaus Müller, Roche Basel
• Prof. François Diederich, ETH
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