Molecular modeling investigations of Eugenol-

Cyclodextrins inclusion complexes

Wichuta RoekmongkolJaruwan Wisarnmetinee

Luckhana Lawtrakul

Sirindhorn International Institute of Technology, Thammasat university

Pure and Applied Chemistry International Conference 2013

Eugenol (EG)• 2-methoxy-4-(2-propen-1-yl)phenol

• Main component extracted from clove oil and other essential

oils.

Clove

Sweet basil Cinnamon leavesEugenol

Extraction

Products

SIIT

Light sensitiveEasily to volatile and oxidized

Cyclodextrins (CD)

• Cyclic oligosaccharide consists of several units of D-glucopyranose

D-Glucopyranose unit Truncated cone Cyclodextrins

Secondary hydroxyl group

Primary hydroxyl group

SIIT

Hydrophobic cavity and hydrophilic outer surface

Application of CD

• Stabilizing agents, solubilizing agents, to obtain

sustained release of drugs and fragrances.

• Pharmaceutical products and food production.

SIIT

Cyclodextrins (CD)

Cyclodextrin Glucopyranose units

Solubility in water at

25°C (mg/L)

Indicative bulk price

($US/kg)

Alpha-CD (αCD) 6 145 45

Beta-CD (βCD) 7 18.5 5

Gamma-CD (γCD) 8 232 80

Hydroxy-propyl βCD (HPβCD)

7 > 600 300

Methylated βCD (MβCD)

7 > 500 350

http://www.eurocdsoc.com/index.php?option=com_content&view=article&id=67 (cited on Oct 23rd 2012)

SIIT

Inclusion complex of EG-CD

• to protect EG from degradation.

• dynamic equilibrium, not permanent.

• Van der Waals, hydrophobic interaction and hydrogen

bonding

CD EG Inclusion complex of EG-CD

SIIT

Scope of work: Molecular simulation

5 hosts

βCD DMβCD TMβCD 2S-HPβCD 6R-HPβCD

Eugenol

1 guestDMβCD TMβCD

2S-HPβCD 6R-HPβCD

SIIT

Methodology

SIIT

Structure construction

Host : 5 βCD derivatives structure from CCDF

Guest: EG was constructed by WebLab ViewerPro.

Pre-docking optimization

GAUSSIAN program

package at PM3 level

GAUSSIAN program

package at HF2-31G level

Molecular docking

simulation

100 runs per each

host-guest pair Fixed

host+flexible guest

All possible complex

structures with binding

energy

Post-docking

simulation

Result from Autodock

EG-βCD EG-DMβCD

EG-TMβCD EG-2S-HPβCD

EG-6R-HPβCD

Conformation 2&3

Structure construction

Host : 5 βCD derivatives structure from CCDF

Guest: EG was constructed by WebLab ViewerPro.

Pre-docking optimization

GAUSSIAN program

package at PM3 level

GAUSSIAN program

package at HF2-31G level

Molecular docking

simulation

100 runs per each

host-guest pair Fixed

host+flexible guest

All possible complex

structures with binding

energy

Post-docking

simulation

PM3

Representative selection

Methodology

SIIT

Representatives’ conformation

EG-βCD EG-DMβCD EG-TMβCD

EG-2S-HPβCD EG-6R-HPβCD

SIIT

Lowest energy, highest frequency

Methodology

SIIT

Structure construction

Host : 5 βCD derivatives structure from CCDF

Guest: EG was constructed by WebLab ViewerPro.

Pre-docking optimization

GAUSSIAN program

package at PM3 level

GAUSSIAN program

package at HF2-31G level

Molecular docking

simulation

100 runs per each

host-guest pair Fixed

host+flexible guest

All possible complex

structures with binding

energy

Post-docking

simulation

Semi-empirical

PM3

HF/2-31G

BSSE: DFT, B3LYP HF/6-

31G

∆E, ∆Ecp

Representative selection

Compounds∆E

(without BSSE)BSSE

∆Ecp

(couterpoise corrected energy)

EG-βCD -49.86 52.01 2.18EG-DMβCD -74.19 49.96 -24.23EG-TMβCD -79.25 65.90 -13.35EG-2S-HPβCD -148.66 80.67 -67.99EG-6R-HPβCD -84.63 68.41 -16.19

Binding energy in kJ/mol at B3LYP/6-31G level

Energy result

∆E 2S-HPβCD>>6R-HPβCD>TMβCD>DMβCD>>βCD

∆Ecp 2S-HPβCD>>DMβCD>6R-HPβCD>TMβCD>>βCD

Interaction capacity

SIIT

• The different result of binding energy from Autodock and post docking optimization

Discussion

Autodock• Fixed host, flexible

guest• TMβCD > 2S-HPβCD

> 6R-HPβCD > DMβCD > βCD

Post docking optimization• Flexible host and guest• 2S-HPβCD >> DMβCD

> 6R-HPβCD > TMβCD >> βCD

SIIT

Discussion

• The substitution of allyl group in MβCD and HPβCD

help to extend the length of βCD's rims.

βCD MβCD HPβCD

SIIT

Discussion

SIIT

∆E 2S-HPβCD>>6R-HPβCD>TMβCD>DMβCD>>βCD64.03 5.38 5.06 24.33

∆Ecp 2S-HPβCD>>DMβCD>6R-HPβCD>TMβCD>>βCD43.76 8.04 2.84 15.53

BEST

Order alternative in the range of 10 kJ

WORST

Discussion• 1:1molar ratio and energetically favorable.

• Stability is provided by

interaction between hydroxyl

groups of EG and CD.

• Major interactions are H-bond

and hydrophobic interaction.

SIIT

H-bond

• The models confirm that EG-βCD is formed in 3 different conformations with the phenyl ring of EG stays inside the host’s cavity whereas

1. The hydroxyl group line toward the primary rim of βCDs and the methoxyl line toward the secondary rim.

Conclusion

βCD

2S-HPβCD

SIIT

2. Hydroxyl group and the methoxyl group of EG are oriented toward the primary rim of βCDs

3. Hydroxyl group and the methoxyl group of EG are oriented toward the secondary rim of βCDs

TMβCD

6R-HPβCD

DMβCD

SIIT

References[1] O. Nuchuchua, S. Saesoo, I. Sramala, S. Puttipipatkhachorn, A.

Soottitantawat, U. Ruktanonchai, Food Research International 42

(2009) 1178-1185.

[2] H.-S. Pilar, L.-M. Santiago, L.-A. Carmen, N.-D. Estrella, Food and

Nutrition Sciences 3 (2012) 716-723.

[3] Y. Yan, X. S. Le, Inclusion Phenomena and Macrocyclic Chemistry

52 (2005) 27-33.

[4] H. Zhan, Z.-T. Jiang, Y. Wang, R. Li, T.-S. Dong, European Food

Research and Technology 227 (2008) 1507-1513.

[5] N. Levine,Quantum Chemistry, Englewood Cliffs, New Jersey:

Prentice Hall (1991), pp. 455–544.

SIIT

[6] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, J. A. Montgomery, Jr., T. Vreven, K. N. Kudin, J. C. Burant, J. M. Millam, S. S. Iyengar, J. Tomasi, V. Barone, B. Mennucci, M. Cossi, G. Scalmani, N. Rega, G. A. Petersson, H. Nakatsuji, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, M. Klene, X. Li, J. E. Knox, H. P. Hratchian, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, P. Y. Ayala, K. Morokuma, G. A. Voth, P. Salvador, J. J. Dannenberg, V. G. Zakrzewski, S. Dapprich, A. D. Daniels, M. C. Strain, O. Farkas, D. K. Malick, A. D. Rabuck, K. Raghavachari, J. B. Foresman, J. V. Ortiz, Q. Cui, A. G. Baboul, S. Clifford, J. Cioslowski, B. B. Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Komaromi, R. L. Martin, D. J. Fox, T. Keith, M. A. Al-Laham, C. Y. Peng, A. Nanayakkara, M. Challacombe, P. M. W. Gill, B. Johnson, W. Chen, M. W. Wong, C. Gonzalez, and J. A. Pople, Gaussian, Inc., Wallingford CT ( 2004).

References

SIIT

[7] T. Steiner, G. Koellner, J. Am. Chem. Soc. 116 (1994) 5122.

[8] T. Aree, H. Hoier, B. Schulz, G. Reck, W. Saenger, Angew. Chem.

Int. Ed. Engl. 39 (2000) 897.

[9] M. R. Caira, V. J. Griffith, L. R. Nassimbeni, B. van Oudtshoorn, J.

Chem. Soc., Perkin Trans. 2 (1994) 2071.

[10] K. Harata, C. T. Rao, J. Pitha, K. Fukunaga, K. Uekama, Carbohydr.

Res. 222 (1991), 37.

[11] K. Harata, C. T. Rao, J. Pitha, Carbohydr. Res. 247 (1993) 83.

[12] K. Harata, C. T. Rao, J. Pitha, Carbohydr. Res. 247 (1993) 83.

[13] J. Stewart, J. Comput. Chem. 10 (1989) 209.

[14] G.M Morris, R. Huey, W. Lindstrom, M. F. Sanner, R. K. Belew, D.

S. Goodsell, A. J. Olson, Comput. Chem. 30 (2009) 2785-279.

References

SIIT

Q&A

SIIT