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SYNERGISTIC COMBINATION OF CASE ALGORITHMS AND DFT CHEMICAL SHIFT PREDICTIONS FOR STRUCTURE ELUCIDATION, VERIFICATION AND REVISION
Alexei V. Buevich (Merck and Co.) Mikhail E. Elyashberg (ACD/Labs)
ACD/Labs NJ Software Symposium
February 7, 2018 Princeton NJ
2
Molecular Structure Analysis
2
Experimental data
Molecular Model
Structure Elucidation Structure Reconstruction
De Novo Structure Analysis
Structure Verification
Computer-Assisted Structure Elucidation
3
Pioneers of Computer-Assisted Structure Elucidations
3
J. Lederberg E. Feigenbaum C. Djerassi
Stanford, USA J. Am. Chem. Soc., 1969, V. 91, p. 2973
M. Munk S-I. Sasaki
Arizona, USA J. Org. Chem., 1969, V. 34, p. 3800
Sendai, Japan Anal. Chem., 1968, V. 40, p. 2220
Moscow, USSR J. Appl. Spectrosc., 1968, v.8, p.696
M.E. Elyashberg L.A. Gribov
4
CASE expert systems based on MS and 2D NMR data
LSD (J.-M. Nuzillard, France) SESAMI (M.E. Munk, USA) CISOC-SES (C. Peng, USA-China) LUCY (C. Steinbeck, Germany) COCON (T. Lindel, Germany) SENECA (C. Steinbeck, Germany) CMC-se (Bruker) Mnova Structure Elucidator (Mestrelab Research) ACD/Structure Elucidator (ACD/Labs)
5
Workflow of ACD/Structure Elucidator algorithm 1) Molecular formula from MS
2) NMR data: 1H, 13C, COSY, HSQC, HMBC
3) Molecular connectivity diagram (MCD)
4) Generation (Strict or Fuzzy) of all possible
constitutional isomers from MCD
5) Empirical chemical shift predictions Fragmental approach (HOSE code based) Method of increments (additive rules) Artificial neural networks (ANN)
6) Ranking structures based on chemical shift deviations:
standard deviation, average deviation, max deviation
M. Elyashberg, A. Williams Computer-based Structure Elucidation from Spectral Data. The Art of Solving Problems. Springer, Heidelberg, 2015, 454 p.
MCD
6
Two types of situations when CASE programs have failed to distinguish the correct structure based on COSY, HSQC and HMBC data
a) the correct structure is on the first position, but its’ average
deviations of chemical shifts are too large (5-6 ppm)
b) the correct structure is either first or among several top-ranked structures with acceptable but very similar deviations
How can CASE algorithms be improved?
7
Incorporate more experimental data:
1,1-ADEQUATE and 1,n-ADEQUATE LR-HSQMBC RDC/RCSA
Improve accuracy of proton/carbon chemical shift predictions
QM
M. Elyashberg, K. Blinov, Y. Smurnyy et al. Magn. Reson. Chem. 2010, 48, 219-229
DFT calculations of NMR chemical shifts
• Recommendations by Rablen, Bally and Tantillo: (http://cheshirenmr.info)
• More than 250 different combinations of functionals and basis sets for nearly all possible situations (limited to organic molecules and natural products)
Scaling factors for calculating chemical shifts (δ) from isotropic shieldings (σ): Scaling factors deemed to take into account the effect of vibrational corrections on chemical shifts (E. E. Kwan and R. Y. Liu JCTC 2015, 11, 5083)
9
CASE-DFT structure elucidation
1) CASE analysis based on MS and NMR data
2) Structures are ranked based on HOSE (NN) predicted carbon chemical shifts
3) Up to Six top-ranked structures by CASE are analyzed by DFT: a) Conformational analysis by MM b) Geometry optimization of the lowest energy conformations by DFT c) Chemical shift calculation by DFT for the lowest energy conformations d) Boltzmann averaging of chemical shifts
4) Structures are ranked based on chemical shifts calculated using DFT
5) The correct structure is selected based on the lowest RMSD (MAE, SD, max_δ or DP4+)
1. Aquatolide (unusual scaffold)
10
OO
O
O
O
O
• Sesquiterpenoid lactone isolated from Asteriscus aquaticus
• Revision was done based on extensive NMR analysis of coupling constants, NOEs, and chemical shifts + DFT analysis of 60 structures + X-ray
1. A. San Feliciano, M. Medarde, J. M. Miguel del Corral, A. Aramburu, M. Gordaliza, A. F. Barrero, Tetrahedron Lett. 1989, 30, 2851. 2. M.W. Lodewyk, C. Soldi, P.B. Jones, M. M. Olmstead, J. Rita, J. T. Shaw, D. J. Tantillo, J. Am. Chem. Soc. 2012, 134,18550.
Original[1] Revised[2]
1989 2012 Asteriscus aquaticus
CASE study of Aquatolide
11
Carbon δCexp δCcalc CHn δHexp JHH, Hz HMBC (H to C) C 1 84.2 87.69 CH 4.48 t(2.2) C 12, C 15, C 3, C 10, C 14 C 2 54.54 49.01 CH 3.26 dd(7.3, 2.5) C 11, C 8, C 3, C 10 C 3 62.83 54.68 C C 4 22.15 31.27 CH2 1.96 m
C 4 22.15 31.27 CH2 2.52 m C 2, C 6, C 10, C 12, C 3, C
5 C 5 28.63 23.36 CH2 2.35 m C 5 28.63 23.36 CH2 2.03 m C 6 131.1 143.34 CH 5.85 ddt(4.7,3.1,1.5) C 4, C 13, C 8 C 7 135.08 136.93 C C 8 211.94 199.27 C
C 9 54.45 51.52 CH 2.92 s C 8, C 7, C 1, C 10, C 2, C
3, C 11
C 10 62.59 49.53 CH 2.64 dd(7.3,1.8) C 11, C 1, C 15, C 8, C 2, C
9, C 14, C 4 C 11 41.86 40.09 C C 12 177.5 176.04 C C 13 22.22 19.56 CH3 1.87 q(2.0) C 7, C 8, C 6 C 14 22.62 12.31 CH3 1.05 s C 15, C 1, C 11, C 10 C 15 22.84 22.77 CH3 1.19 s C 11, C 14
MCD
1H, 13C, COSY, HSQC, HMBC
CASE study of Aquatolide
12
• Only three structures were generated by ACD/Structure Elucidator (tg=0.05s)
• No original structure in the output file (!)
• The revised structure is ranked first, but all three structures have large chemical shift deviations
revised
CASE-DFT study of Aquatolide
13
The lowest RMSD and max_δ are predicted for the revised structure (!)
CH3
H3CCH3
O
O
O
6
10
4
5
78 H3C
CH3
CH3
O
O
O12
23
1
119
15
14
13
6
104
5
7
8
12
2
3
1
11
9
15
14
13
H3C CH3
O
O
O
6
10
45
7
8
12
2
3
1
119
1514
13
Structure #1 (2) Structure #2 Structure #3
Experimental Structure #1 Structure #2 Structure #3 Carbons δCexp δCcalc δCcalc δCcalc
C 1 84.2 83.28 87.38 85.33 C 2 54.54 54.53 69.43 53.46 C 3 62.83 63.17 54.56 45.07 C 4 22.15 22.80 36.46 22.29 C 5 28.63 30.69 33.12 32.50 C 6 131.1 135.07 160.44 146.18 C 7 135.08 137.29 132.61 138.82 C 8 211.94 211.99 197.42 201.88 C 9 54.45 54.97 55.04 49.13
C 10 62.59 64.91 79.42 50.35 C 11 41.86 44.91 48.70 48.82 C 12 177.5 177.40 172.69 176.12 C 13 22.22 22.94 13.69 16.92 C 14 22.62 20.63 19.75 18.37 C 15 22.84 20.89 25.47 27.87
RMSD, ppm 1.82 11.38 7.65 max_δ, ppm 3.97 29.34 17.76
Gaussian09: mPW1PW91-PCM/6-311+G(2d,p)//B3LYP/6-31+G(d,p) A.V. Buevich, M. E. Elyashberg, J. Nat. Prod. 2016, 79, 3105.
Lessons of Aquatolide story
14
CASE analysis would have prevented the publication of erroneous structure CASE analysis significantly reduces the number of potential structures that needs to be verified by DFT calculations
CH3
H3CCH3
O
O
O
6
10
4
5
78 H3C
CH3
CH3
O
O
O12
23
1
119
15
14
13
6
104
5
7
8
12
2
3
1
11
9
15
14
13
H3C CH3
O
O
O
6
10
45
7
8
12
2
3
1
119
1514
13
Structure #1 (2) Structure #2 Structure #3
M.W. Lodewyk, C. Soldi, P.B. Jones, M. M. Olmstead, J. Rita, J. T. Shaw, D. J. Tantillo, J. Am. Chem. Soc. 2012, 134,18550.
A.V. Buevich, M. E. Elyashberg, J. Nat. Prod. 2016, 79, 3105.
Structure determined based
on CASE-DFT
2. Coniothyrione (proton-deficient)
15
• The original structure of coniothyrione (isolated from an extract derived from a strain of Coniothyrium cerealis MF7209) was proposed based on the absence of HMBC cross-peak between olefinic proton H4 and carbonyl carbon C1 (!).
• The structure of coniothyrione was revised based on 1,1-ADEQUATE experiments and DFT analysis of JCC, JHC couplings, and carbon chemical shifts.
3. Ondeyka, J. G.; Zink, D.; Basilio, A.; Vicente, F.; Bills, G.; Diez, M. T.; Motyl, M.; Dezeny, G.; Byrne, K.; Singh, S. B. J. Nat. Prod. 2007, 70, 668. 4. Kong, F.; Zhu, T.; Pan, W.; Tsao, R.; Pagano, T. G.; Nguyen, B.; Marquez, B. Magn. Reson. Chem. 2012, 50, 829. 5. Martin, G. E.; Buevich, A. V.; Reibarkh, M.; Singh, S. B.; Ondeyka, J. G.; Williamson, R. T. Magn. Reson. Chem. 2013, 51, 383.
Original[3] Revised[4,5]
2007 2012, 2013
O
OH O HO
Cl
O
O12
4
13
8O
OH O HO
Cl
O
O
CASE study of Coniothyrione
16
Carbon δC δC calc XHn δH JHH, Hz HMBC (H to C) C1 168.7 172.74 C C2 79.8 78.01 C C3 127.2 132.49 C C4 143.1 129.25 CH 7.2 s C2, C5, C14 C5 164.5 154.7 C C7 155.7 156.53 C C8 108.1 108.9 CH 7.22 d(8.5, 1.0) C10, C12 C9 135.8 137.35 CH 7.7 t(8.5) C7, C11
C10 112.7 112.14 CH 6.9 dd(8.5, 1.0) C8, C12 C11 160.6 160.56 C C12 110.7 109.78 C C13 176 175.24 C C14 120.8 114.22 C C15 52.9 51.97 CH3 3.64 s C1 O1 OH 12.4 s C10, C11, C12
CH352.90(ob)
C79.80(ob) CH
108.10
C110.70
CH112.70
C120.80
C127.20
CH135.80
CH143.10
C155.70
C160.60(ob)
C164.50(ob) C
168.70(ob)
C176.00(ob)
O
O
O
O
OOH
Cl
H
MCD
Coniothyrione is a proton-deficient molecule C14H9ClO6 No ADEQUATE data were used in CASE study (!)
CASE study of Coniothyrione
17
CH3
OH
O
O
O
O
OH
Cl
dA(13C): 3.137dN(13C): 3.480dI(13C): 5.351max_dA(13C): 15.130
#1 CH3
OH
O
O
O
O
OH
Cl
dA(13C): 3.410 dN(13C): 3.072dI(13C): 3.398max_dA(13C): 13.850
#2 CH3
OH
O
O
O
O
OH
Cl
dA(13C): 3.556 dN(13C): 3.195dI(13C): 4.122max_dA(13C): 11.530
#3
CH3
OH
OO
O
O
OHCl
dA(13C): 3.594 dN(13C): 3.406dI(13C): 4.717max_dA(13C): 8.320
#4
CH3
OH
O
O
O OOH
Cl
dA(13C): 3.689 dN(13C): 3.372dI(13C): 4.155max_dA(13C): 9.050
#5
CH3
OH
OO
O
OOH Cl
dA(13C): 3.861 dN(13C): 2.750dI(13C): 2.723max_dA(13C): 14.910
#6
Revised
157803 structures were generated by ACD/Structure Elucidator, only 14976 passed spectral and structural filtering (tg=1 min) The revised structure was ranked second (!), the original structure was ranked 18th
A.V. Buevich, M. E. Elyashberg, J. Nat. Prod. 2016, 79, 3105.
CASE-DFT study of Coniothyrione
18
Exper. Structure
#1
Structure #2
(revised) Structure
#3 Structure
#4 Structure
#5 Structure
#6 Labels δC δCcalc δCcalc δCcalc δCcalc δCcalc δCcalc
1 168.7 171.3 172.0 165.9 165.6 164.0 160.4 2 79.8 81.6 79.6 69.6 85.1 84.4 102.9 3 127.2 142.7 135.6 146.1 147.1 140.9 156.3 4 143.1 125.4 144.9 134.1 135.8 136.1 125.7 5 164.5 171.0 163.8 160.8 155.7 163.8 164.1 7 155.7 154.6 154.7 158.8 160.3 159.6 154.7 8 108.1 105.3 105.5 105.3 101.5 103.8 105.7 9 135.8 134.8 134.3 125.3 126.4 126.7 134.1
10 112.7 111.9 112.0 106.5 108.9 109.1 111.8 11 160.6 160.5 160.5 145.3 150.2 148.9 160.8 12 110.7 109.8 110.3 110.2 108.8 108.6 110.1 13 176.0 173.9 172.9 159.1 173.1 180.5 172.3 14 120.8 117.2 120.6 121.1 124.7 122.7 117.3 15 52.9 54.1 53.7 53.8 53.2 51.7 52.0
RMSD - 6.75 2.76 9.46 7.86 6.40 11.29 max_δ - 17.71 8.39 18.94 19.87 13.67 29.07
Only top 6 structures had to be analyzed by DFT (!) The lowest RMSD and max_δ are predicted for the revised structure #2 (!) (Structure #1 was also rejected based on JCH-coupling analysis)
Gaussian09: mPW1PW91-PCM/6-311+G(2d,p)//B3LYP/6-31+G(d,p)
O
OH O HO
Cl
O
O12
413
89
1011 12
7
14
5 3
#1 #2
15
OHO
Cl
O
O
OOH
12
413
8
9
1011 12
7
14
5
3
15
OH
1
2
4
13
8
9
1011 12
7
14
5
3
15
O
O OH
Cl
O O
OH
1
2
4
138
9
1011 12
7
14
5
3
15
O
O O
OH
O Cl
OH 1
2
4
138
9
1011 12
7
14
5
3
15
OOH
O Cl
O
OO
OH O HO
1
2
413
89
1011 12
7
14
5 3
15
Cl
OO
#3 #4
#5 #6
A.V. Buevich, M. E. Elyashberg, J. Nat. Prod. 2016, 79, 3105.
3. Oroidin (heavy atoms)
19
• Oroidin (C11H10Br2N4O), a highly proton-deficient bromopyrrole (5), was isolated from the sponge Agelas oroides
• Oroidin has been extensively studied by IR, NMR, X-ray crystallography and was confirmed by direct synthesis
• The structure of oroidin was conclusively identified by the decidedly lowest average deviations by COCON program6
6. M. Köck, J. Junker, T. Lindel, Org. Lett. 1999, 1, 2041-2044. 7. T. Lindel, J. Junker, M. Köck, Eur. J. Org. Chem. 1999, 573-577 8. S. Rasapalli, V. Kumbam, A. N. Dhawane, J. A. Golen, C. J. Lovely, A. L. Rheingold, Org. Biomol. Chem. 2013, 11, 4133-4137.
NH
O
Br
Br HN N
NHNH2
3
2
4
5
Agelas oroides 5
CASE study of Oroidin
20
156 structures were predicted by ACD/Structure Elucidator
Correct structure of oroidin was ranked first, though structure #3 had very similar average deviations and max_δ, thus prompting DFT analysis
NH
O
Br
Br HN N
NHNH2
3
2
4
5
NH2
NH
NH
NHN
O
BrBr
NH2
NH
NH
NHN
O
BrBr4
5
NH2
NH
NH
NHN
O
Br
Br
NH2
NH
NH
NHN
O
Br
Br
5
correct
CASE-DFT study of Oroidin
21
Three top-ranked structures were calculated using SPARTAN program (H, C, N, O, S, Si, P, F, Cl, Br) The lowest RMSD and max_δ are predicted for the correct structure 5 SPARTAN: EDF2/6-31G(d)//B3LYP/6-31+G(d,p)
Carbons Exp. 6 (5) 7 (5-3) 8 (5-4) 2 128.0 127.7 128.8 126.7 3 113.0 111.4 117.2 121.0 4 98.0 100.1 97.8 100.2 5 105.0 102.6 97.9 103.4 6 159.0 161.4 161.5 161.2
RMSD, ppm - 1.93 3.87 3.95 max_δ, ppm - 2.4 7.1 8.0
HNBr
O
HN
Br 32
4
5 6
HNBr
BrO
HN
3 24
5 6
HN
BrO
HN
Br
3
2
45
6
A.V. Buevich, M. E. Elyashberg, Magn. Reson. Chem. 2017, DOI: 10.1002/mrc.4645
4. Epoxyroussoenone (proton-deficient and chiral)
22
• Epoxyroussoenone (11) was isolated from a culture broth of Roussoella japanensis KT1651.
• Structure was determined using 1D and 2D NMR spectroscopy supported by DFT calculations of 13C chemical shifts and ECD spectra. Configuration was determined based on NOE and ECD data.
• Only two alternative structures, 11 and 12, have been examined, which appears to be insufficient considering its proton-deficient nature (C15H14O7).
Honmura, Y.; Takekawa, H.; Tanaka, K.; Maeda, H.; Nehira, T.; Hehre, W.; Hashimoto, M. J. Nat. Prod. 2015, 78, 1505-1510
1
4
9
76
3
O
OH
O
OH
OH
O
O
OHOOH
OO
HO
O
10
5
11 12
CASE study of Epoxyroussoenone
23
CH321.05(fb)
CH355.41(ob) C
61.81(ob)
CH65.09(ob) CH
68.45(ob)
C88.25(ob)
CH103.31(fb)
CH104.53(fb) CH
104.70(fb)
C108.51(fb)
C134.58(fb) C
158.39(ob)
C161.30(ob)
C170.26(ob)
C189.12(ob)
OO
OO
OHOH
OH
MCD
CH3
CH3
OH OH
OH
O
O
O
O
dA(13C): 1.343 dN(13C): 2.050dI(13C): 2.394max_dA(13C): 4.440
#1
CH3CH3
OH OH
OH
O
O
O
O
dA(13C): 2.172 dN(13C): 2.004dI(13C): 2.448max_dA(13C): 8.620
#2
CH3
CH3
OH
OHOHO
O
O
O
dA(13C): 2.199 dN(13C): 2.340dI(13C): 3.308max_dA(13C): 7.040
#3
CH3
CH3
OH OHOH
O
O
O
O
dA(13C): 2.287 dN(13C): 2.335dI(13C): 3.221max_dA(13C): 7.310
#4
CH3
CH3
OH OHOH
OO
O
O
dA(13C): 2.429 dN(13C): 3.409dI(13C): 3.466max_dA(13C): 8.720
#5
CH3CH3
OH
OHOHO
O
O
O
dA(13C): 2.692 dN(13C): 2.931dI(13C): 2.947max_dA(13C): 8.840
#6
1500 structures were generated by ACD/Structure Elucidator, only 13 passed spectral and structural filtering (tg=1 s). The correct structure was ranked second (!). The alternative structure 11 was rejected (124th position). Instead, 6 plausible structures would need to be examined.
correct
A.V. Buevich, M. E. Elyashberg, J. Nat. Prod. 2016, 79, 3105.
CASE-DFT study of Epoxyroussoenone
24
4 diastereomers (A, B, C, D) for each of the top-ranked six structures were analyzed by DFT Structures #1 and #2 may have two conformations. Only chemical shifts of the lowest energy conformations were used. Correct isomer is #2A
O
OH
O
OH
OH
O
OO
OH
O
OH
OH
O
OO
OH
O
OH
OH
O
OO
OH
O
OH
OH
O
O
O
OH
OH
O
O
OH
O
O
OH
OH
O
O
OH
O
O
OH
OH
O
O
OH
O
O
OH
OH
O
O
OH
O
OH
OH
OOH
O
O
O
OH
OH
OOH
O
O
O
OH
OH
OOH
O
O
O
OH
OH
OOH
O
O
O
OHOH
O
O
O
OH
O
OHOH
O
O
O
OH
O
OHOH
O
O
O
OH
O
OHOH
O
O
O
OH
O
OOH
O
OH
O
O
OOH
O
OH
O
O
OOH
O
OH
O
O
OOH
O
OH
O
O
OH OH OH OH
OOH
O
O
OHO
OH
OOH
O
O
OHO
OH
OOH
O
O
OHO
OH
OOH
O
O
OHO
OH
#1A #1B #1C #1D
#2A #2B #2C #2D
#3A #3B #3C #3D
#4A #4B #4C #4D
#5A #5B #5C #5D
#6A #6B #6C #6D
A.V. Buevich, M. E. Elyashberg, J. Nat. Prod. 2016, 79, 3105.
CASE-DFT(13C) study of Epoxyroussoenone
25
RMSD and max_δ between experimental and DFT-calculated δ(13C) for six top-candidate structures of epoxyroussoenone and their stereoisomers A, B, C and D The lowest RMSD and max_δ were found for the first two top-ranked structures. The correct #2A structure has similar RMSD with #2B and #1B.
0.00
2.00
4.00
6.00
8.00
10.00
12.00
14.00
16.00
1A 1B 1C 1D 2A 2B 2C 2D 3A 3B 3C 3D 4A 4B 4C 4D 5A 5B 5C 5D 6A 6B 6C 6D
RMSD
and
max
_δ, p
pm
Structures
RMSD
max_δ
Gaussian09: mPW1PW91-PCM/6-311+G(2d,p)//B3LYP/6-31+G(d,p) A.V. Buevich, M. E. Elyashberg, J. Nat. Prod. 2016, 79, 3105.
CASE-DFT(13C) study of Epoxyroussoenone
26
RMSD(C5,C10) and ∆∆δ(C5,C10) for the most critical C5 and C10 carbon chemical shifts were calculated. The lowest RMSD(C5,C10) and ∆∆δ(C5,C10) were found for the correct structure and correct isomer #2A (11).
Gaussian09: mPW1PW91-PCM/6-311+G(2d,p)//B3LYP/6-31+G(d,p)
0
5
10
15
20
25
1A 1B 1C 1D 2A 2B 2C 2D 3A 3B 3C 3D 4A 4B 4C 4D 5A 5B 5C 5D 6A 6B 6C 6DRM
SD(C
5,C1
0) a
nd ∆
∆δ(
C5,C
10),
ppm
Structures
RMSD(C5,C10)
∆∆δ(C5,C10)O
OH
O
OH
OH
O
O10
5
O
OH
OH
O
O
10
5OH
O
#1 #2
∆∆δ(C5,C10) = |(∆δ(C5,C10)exp - ∆δ(C5,C10)calc|
A.V. Buevich, M. E. Elyashberg, J. Nat. Prod. 2016, 79, 3105.
CASE-DFT(1H) study of Epoxyroussoenone
27
RMSD(OH) and max_δ(OH) for 1H chemical shifts of the three OH groups in four diastereomers of the six top-ranked structures of epoxyroussoenone The lowest RMSD(OH) and max_δ(OH) were found for the correct structure and correct isomer #2A (11).
0
1
2
3
4
5
6
7
8
1A 1B 1C 1D 2A 2B 2C 2D 3A 3B 3C 3D 4A 4B 4C 4D 5A 5B 5C 5D 6A 6B 6C 6D
RMSD
(OH)
and
max
_δ, p
pm
Structures
RMSD(OH)
max_δ
OH
OH
OOH
O
O
O
OHOH
O
O
O
OH
O
OOH
O
OH
O
O
OH OOH
O
O
OHO
OH
O
OH
O
OH
OH
O
OO
OH
OH
O
O
OH
O
#1 #2
#5 #6
#3 #4
(M. G. Chini, R. Riccio, G. Bifulco Eur. J. Org. Chem. 2015, 1320)
A.V. Buevich, M. E. Elyashberg, J. Nat. Prod. 2016, 79, 3105.
Conclusions
28
Synergistic combination of CASE and DFT:
Addition of the DFT to CASE expert systems broadens the range of amenable to CASE structural problems: - molecules with unusual scaffolds - configurational isomers - conformationally flexible molecules (A.V. Buevich & M.E. Elyashberg MRC 2017, DOI: 10.1002/mrc.4645) DFT-based analysis of molecular structures as a method of structure verification in combination with CASE becomes a true structure elucidation method
Acknowledgments
29
Gary Martin (Merck) Thomas Williamson (Merck) Ryan Cohen (Merck) Dimitris Argyropoulos (ACD/Labs) Dean Tantillo (UCD) Masaru Hashimoto (Hirosaki University)
THANK YOU