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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