Post on 30-Jul-2020
What Crystal Structure Databases Tell us about Conformations of Drug-like Molecules
Martin Stahl, Roche Basel, June 2008
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
Required GeneralizationsStatistics over Recurring Fragments
ON
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
Cis or Trans? From Amides to Electrostatic Repulsion
Generalized Allylic Strain
The Sulfonyl Group
Properties of Aniline Derivatives
Project Example: New F.VIIa Inhibitors
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
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
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
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:
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).
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
Cis or Trans? From Amides to Electrostatic Repulsion
Generalized Allylic Strain
The Sulfonyl Group
Properties of Aniline Derivatives
Project Example: New F.VIIa Inhibitors
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
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
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
τ = 110˚
τ = 0˚
MYCPHA1jr1 (IMPDH Complex Structure)
Allylic Strain in ActionThe Example of Mycophenolic Acid
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
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
ZOWWEN CAGDUKZOHNUF
Tertiary AmidesSubstituents Point out of Plane
BOAYPI
Acylated PiperidinesEnforcement of Axial Substituents
REYPUG
Acylated Piperidines and Related StructuresPDB Examples
MQPA – thrombin complex (1etr) DPPIV complex, J. Med. Chem. 2008, 51, 589–602
FKBP12 complex structure (1j4i)
Acylated PiperidinesAnalogous Effects with Sulfonamides
Cis or Trans? From Amides to Electrostatic Repulsion
Generalized Allylic Strain
The Sulfonyl Compounds
Properties of Aniline Derivatives
Project Example: New F.VIIa Inhibitors
Sulfonamides are not Amide Isosteres!
FIBKUWPABZAM
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
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
PKA fivefold mutant model of Rho-Kinase complexed with fasudil (2gni, left) andan analog (2gnh, right).
Aryl-Sulfonyl CompoundsExtreme Cases of ortho Substitution
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
HPTZDXVOGKILHHBPTH
WABYIH HITQOQ CADTOQ
Aryl-Sulfonyl CompoundsPreferred S-N Torsion leads to Axial N Substituents
Farnelyltransferase complex (1sa5) Stromelysin complex (1ciz)
Sulfonamide Special EffectsLonger Bond Distances Allow Folding Back
Cis or Trans? From Amides to Electrostatic Repulsion
Generalized Allylic Strain
The Sulfonyl Compounds
Properties of Aniline Derivatives
Project Example: New F.VIIa Inhibitors
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
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
LOSQEP
NAXDAR
Cyclic Aniline DerivativesPyramidalization Strongly Affects Molecular Shape
DUBXAZICOKOA
ZUHRID01
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
Cis or Trans? From Amides to Electrostatic Repulsion
Generalized Allylic Strain
The Sulfonyl Group
Properties of Aniline Derivatives
Project Example: New F.VIIa Inhibitors
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
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
NH2 NH
NH
OO
NH2 NH
NH
OO
inactive 11 μM
New F.VIIa InhibitorsDesign of a New Scaffold, Second Iteration
NH2 NH
NH
OO
FO
1.7 μM
New F.VIIa InhibitorsConfirmed Binding Mode of Mandelic Acids
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
HCV polymerase palm site complex (2qe5) locked: 11bHSD-1 complex (2irw)
Alkoxymethyl AmidesPDB Examples
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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