Impressions of Spectrus Workbook ASV tools – did they improve?

ACD/Labs NMR Software Symposium Alex De Groot

SMASH September 22 - 2013

Intro

NMR at Janssen Belgium: • Discovery: 2 NMR specialists (1.7 FTE), ±40 chemists in Open Access • Development: 5 NMR specialists, ±20 chemists • ACD/Labs software version 12.0

Evaluating ASV systems for 3 years

Beta-tester for ACD/Spectrus platform. Only one who works with ACD/NMR Workbook Frequent feedback to ACD/Labs about bugs, suggestions,

improvements...

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Part 1 : Impressions of ACD/Spectrus

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– Previously: • Interpreting proton spectrum • Looking to and from time to time transferring assignments to 2D

– ACD/NMR Workbook v12.01: • Assignments automatically transferred: great! But...

Lot of problems with overlap, difficult to correct Spend more time in correcting than benefit of transfer Disadvised colleagues to start working with workbook

– ACD/NMR Workbook v2012 (Spectrus): • More automation and much better automatic results • Problematic peaks easier remediated Whole other way of working:

Everything automatic Check for not picked peaks and not assigned ones Get out issues based on red arrows on structure

Great for giving feedback to doubting chemists

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Whole other way of working

17N22

21

20 19

16

14N18

N15

5

Cl23

24

25

CH3 26

CH328

N4

6

N1

2

3

7 10

11

8 9

CH312O

H3a

H5a

17N22

21

20 19

16

14N18

N15

5

Cl23

24

25

CH3 26

CH328

N4

6

N1

2

3

7 10

11

8 9

CH312O

H3a

H5a

13C-HMBC

15N-HMBC

Whole other way of working

DBU:

R600109_1H.esp53 H's / 53 H's (spectra / structure)

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5Chemical Shift (ppm)

2.002.2011.632.571.153.185.194.068.051.022.021.000.991.002.020.980.901.841.001.011.011.00

CHLOROFORM-d

21,23,30,31

5

20

47

6

48,49

3

422

35 48,49

41

18

7

43

40

25

13,24

37

7

14

19,8

17,46

32,19,6,8

9.40

9.40

8.77

8.77

8.58

8.57

8.57

8.31

8.29

7.84 7.

827.

81

7.49

7.47

5.60 5.60

5.59

5.58

5.57

5.57

4.82

4.80

4.80

4.78

4.66

4.66

3.96

3.95

3.93

3.68

3.67

3.66

3.65

2.97 2.

96

2.95

2.95 2.94

2.89

2.88

2.88

2.75

2.74

2.73

2.72

1.97 1.96

1.95 1.

901.

891.

88 1.84

1.83

1.75

1.63

1.61

1.51

1.43

1.41

1.40

1.31

1.30

1.23

1.20

1.08

1.02

0.93

0.92

0.91

0.87

0.76

0.75

0.74

0.73

0.72

41

40

N42

N39

38

43

26

O27

NH25 24

15

32

NH14

O16

33 37

13

3435

36

9

22

O10

N1

2330

31

5

24

11

3

6

8

7

O12

NH1718

2819

44

O2920

O45

NH46

47

48 49

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Telaprevir

SOP and Points of attention:

• Reference H (and C) and dark region solvent peaks

• Auto allign Verify all 2D are alligned well in both dimensions!

• Auto signal analysis Assure all 2D are picked well, especially NOESY!

• Auto assign

• Check out all strange connection arrows in all 2D and wrongly coulored atoms

atahri_440_2.003.001.2rr.esp

4.0 3.9 3.8 3.7 3.6 3.5 3.4 3.3 3.2F2 Chemical Shift (ppm)

38

40

42

J(3.29, 37.8, 0) (5a, 5)

H(4.05, 42.23, 0) (3a, 3)

HSQC-ed

Improvement opportunities

• Taking the already picked 2D’s into account for the automatic assignment.

E.g.: Splitted CH2 assigned to two proton multiplets which are not on the same carbon

• Suggestions from you?

Part 2 : ASV tools – did they improve?

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NMR at Discovery Janssen Belgium

Open access:

80% of approvals done by chemists themselves

20% request for expert help > 25% of these are wrong

So only 5% is wrong????

We do not check but we “accidentally” encounter errors...

14

15

ORN

Cl

C

F

N

Cl

C

F

N

Cl

C

F

.....wrong top aromatic ring delivered

16

CH3

CH3

O

CH2 NH

CH2

CH3

CH3

O H

CH2 N

CH2

Aliphatics very symmetric; exchangeable was a sharp singlet! .....11 products assumed by chemist to be closed as macrocycles...

What about external chemistry???

In 2011: 47 wrong external compounds found!

....and we even did not search for it...

few examples of wrong starting materials used for internal reactions:

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N+

O-

O

N

Br

N+

O-

O

N

Cl

NN

N

N

F

FF

NN

N

NH

F

FF

external CRO chemistry wrong (few examples)

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CH3

N

N

CH3

NCH3

CH3

CH3

NHN

CH3NHCH3

CH3

N

NH

O

CH3

NH

N

NH

O

NHCH3

NHR

N

R1

R2 OH

O

NR

N

R1

R2

OH O

CRO: bigger problems – fast check on request of chemist > very obvious ortho-meta error found:

Already 23 analogue compounds synthesized in CRO, with NMR measured!

All showed 2 triplets, but no CRO chemist/analyst has ever seen these not matching peaks????

Those 23 were already screened internally and were at risk of influencing chemistry design.

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EO7218_17_001.001.001.1R.esp

8.3 8.2 8.1 8.0 7.9 7.8 7.7 7.6 7.5 7.4 7.3 7.2 7.1 7.0 6.9 6.8 6.7 6.6 6.5

R

OCH3

R

O

CH3

Magic?

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Automated Structure Verification

or Pandora’s box?

• 3 vendors evaluated : ACD/Labs, Mnova and Bruker

• Not focused on big numbers, but on getting an idea of trustworthiness, reliability, structural insight, efficiency, problems and ease of use

• 2 sets of compounds: – fragment compounds → 3 wrong sets designed

– Wrong chemistry compounds

• 2 screening techniques: 1H, 1H+HSQC

• 2 alterations: prediction training, concurrent verification

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ASV test at Janssen

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Figure 1: Example of structures

used for false positive evaluation

Set I Set II

• 37 molecules • Fragment library • 1 correct structure + 3 invented wrong structures

• 77 molecules • Synthesized by chemists • 1 correct structure:

real structures elucitated by NMR expert

• 1 wrong structure: proposed by chemists

Testsets

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Main screen of ACD/NMR Expert

Traffic light colors- match factor

ClN

N

N

S

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1H verification set I (fragments)

Comparison between ACD/Labs new and old version

1D- Improvement multiregio isomers

ACD/Labs with or without training

training not real improvement

86%

41%

58%

10%

78%

34%

44%

9%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

besttautomere

hetero regio multiregio

1D new

1D training new

86%

41%

58%

10%

81%

41%

59%

35%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

besttautomere

hetero regio multiregio

1D ACD new

1D ACD old

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1D ACD labs better mutiregio, while still high pass rate

Set 1: 1D – comparison ACD/Labs v2012, CMC assist v2, Mnova v 8.1:

86%

41%

58%

10%

78%

54%

62%

30%

57%

16%

38%

19%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

correct hetero regio multiregio

ACD SpectrusCMC AssistMnova

1H verification Set I (fragments)

Adding 2D-HSQC-edited information

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27

set I, combined 1D+ HSQC verification

Comparison between ACD/Labs old and new, and Mnova 8.1

86%

41%

58%

10%

81%

43%

62%

16%

68%

16%

35%

7%

49%

14%

27%

5%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

correct hetero regio multiregio

ACD 1D newACD comb. oldACD comb. newMnova

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new version better in regioisomers, but more ambiguous

Set I - 1D- concurrent verification, comparison new and old version

ACD Manual concurrent verification

49%

5%

19%

0%

27% 32%

8% 3%

0%

57%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

correct hetero regio multiregio ambiguous

ACD oldACD new

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Set I – combined 1D+2D concurrent verification : comparison new and old version

41%

16%

5% 0%

38%

65%

0% 0% 0%

35%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

correct hetero regio multiregio ambiguous

ACD oldACD new

ACD Manual concurrent verification

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Set 2: chemistry compounds

Set II - 1D verification: Comparison between new ACD, Mnova and CMC

49%

23% 17% 17%

49%

32%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

correct wrong

ACD SpectrusMnovaCMC assist

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Set 2: chemistry compounds

Set II – Combined 1D& HSQC verification: comparison ACD/Labs,

CMC assist, Mnova and ACD/Labs manual concurrent

62%

9%

21%

5%

52%

30%

69%

2%

0%

10%

20%

30%

40%

50%

60%

70%

80%

correct wrong

ACDMnovaCMC assistACD concurrent

30%

3%

61%

82%

9% 6% 9%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

correct wrong

fitno fitseveralgood suggested

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Set 2 – combined 1D+2D automatic concurrent verification

ACD/Labs automatic concurrent verification (β-version!)

– 10 isomers invented - 5-step verification

– Alternative structure between isomers: • 9% for good and 12% for wrong

Conclusions – Many failures still from processing!

– ACD/Labs has best equilibrium pass rate/false positives

– Mnova has many colors, but with suggested cut-off of 0.3 low pass rates are observed

– CMC-assist is different, but higher number of false positives are observed

– General performance conclusion: • all good to find big mistakes in structures, but all have hard time with

common regio-isomers discrimination • No magic: still a lot of false positives, especially for proton only

we cannot fully rely on it • Better than nothing: every error is one out Good for checking CRO data, but we are afraid chemists would take

green blindly for granted

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Automated Structure Verification

Aknowledgements

My students:

Benjamin Guguen (2011)

Léa Drieu (2012)

Nicolas Lefèvre (2013)

ACD macro tools support

Sergey Golotvin

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Thank you!

Questions?