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
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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
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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.
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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)
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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
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Scope of work: Molecular simulation
5 hosts
βCD DMβCD TMβCD 2S-HPβCD 6R-HPβCD
Eugenol
1 guestDMβCD TMβCD
2S-HPβCD 6R-HPβCD
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Methodology
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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
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
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Representatives’ conformation
EG-βCD EG-DMβCD EG-TMβCD
EG-2S-HPβCD EG-6R-HPβCD
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Lowest energy, highest frequency
Methodology
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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
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• 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
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Discussion
• The substitution of allyl group in MβCD and HPβCD
help to extend the length of βCD's rims.
βCD MβCD HPβCD
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Discussion
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∆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.
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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
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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
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