Computational Study on the Molecular Inclusion Of

Supporting Information

For

Computational Study on the Molecular Inclusion of

Andrographolide by Cyclodextrin

Hongwei Zhou,1 Wai-Ping Lai,1 Zhiqiang Zhang,1 Sze-Chun Li,1Wai-Kee Li,2 Hon-Yeung Cheung1,3

1Research Group for Bioactive Products, Department of Biology and Chemistry,

City University of Hong Kong, Kowloon, Hong Kong

2Department of Chemistry, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong

3 To whom correspondence should be addressed (e-mail address: )

Table of Contents

Items / Memo / Page
Fig. I / FTIR (Fourier-transform infrared spectroscopy) spectrum of spray dried Particles with different molar ratio of andro and CDs. PM: physical mixture; SD: spraying dry. / S2
Table I / Table I: Fourier-Transform Infrared Spectroscopy (FTIR) Stretching Band (cm-1) of Andro in Physical Mixtures and Spray Dried Products With βCD and γCD / S3
Table II / The Stability and the Rate Constants of Andrographolide at 80℃ / S3
Table III / Dissolution Efficiency at 120 min, DE 120 of Andro, Andro:CDs Physical Mixture and Their Spray Dried Products / S4
Table IV / Table IV: The Binding Energies (in kcal mol-1) and the Docking Energies (n kcal mol-1) of the Conformation Instances in the Preliminary Docking Experiment. / S4
Table V / The Bond Path Length (BPL, in Å), the Electron Density (r) and Laplacian of (Ñ2r) of Hydrogen Bond in Andro:αCD1 / S5
Table VI / The Bond Path Length (BPL, in Å), the Electron Density (r) and Laplacian of (Ñ2r) of Hydrogen Bond in Andro:αCD2 / S6
Table VII / The Bond Path Length (BPL, in Å), the Electron Density (r) and Laplacian of (Ñ2r) of Hydrogen Bond in Andro:βCD1 / S7
Table VIII / The Bond Path Length (BPL, in Å), the Electron Density (r) and Laplacian of (Ñ2r) of Hydrogen Bond in Andro:βCD2 / S8
Table IX / The Bond Path Length (BPL, in Å), the Electron Density (r) and Laplacian of (Ñ2r) of Hydrogen Bond in Andro:γCD1 / S9
Table X / The Bond Path Length (BPL, in Å), the Electron Density (r) and Laplacian of (Ñ2r) of Hydrogen Bond in Andro:γCD2 / S10

Fig. I. FTIR (Fourier-transform infrared spectroscopy) spectrum of spray dried Particles with different molar ratio of andro and CDs. PM: physical mixture; SD: spraying dry.

Table I. Fourier-transform infrared spectroscopy (FTIR) stretching band (cm-1) of andro in physical mixtures and spray dried products with βCD and γCD

βCD / γCD
-C=O / -C=C- / -C=O / -C=C-
Andro / 1727 / 1676
Physical mixture
1:1 / 1727 / 1673 / 1727 / 1673
1:2 / 1727 / 1674 / 1727 / 1673
Andro:CD complex
1:1 / 1727 / 1672 / 1739 / 1671
1:2 / 1743 / 1663 / 1739 / 1670

Noted that, in 1:1 Andro: βCD, the stretching band have no change, indicating –C=O and –C=C– of Andro have no interaction with CD because their stretching bands are not changed. That is, the decalin moiety of Andro be encapsulated inside CD, while in 1:2 Andro: βCD, both the decalin moiety and the lactone moiety be encapsulated inside CD. So as to 1:1 and 1:2 Andro: γCD.

Table II. The stability and the rate constants of andrographolide at 80℃

Types of sample preparation / Mixed types and ratio / Conditions of spray drying / pH2 / pH7 / pH8
Inlet
Temperature (℃) / Feed rate
(ml/min)
Pure Andro / - / - / - / 0.0938 / 0.1202 / 0.7994
Spry drying / Andro:βCD(1:2) / 150 / 5 / 0.0376 / 0.0735 / 0.5549
Spry drying / Andro:γCD(1:2) / 150 / 5 / 0.0201 / 0.0686 / 0.7750
Physical mixture / Andro:βCD(1:2) / - / - / 0.0704 / 0.1322 / 0.6164
Physical mixture / Andro:hpβCD(1:2) / - / - / 0.1053 / 0.1445 / 0.5479
Physical mixture / Andro:γCD(1:2) / - / - / 0.1064 / 0.1372 / 0.7766
Spry drying / Andro:βCD(1:2) / 150 / 10 / 0.0707 / 0.0951 / 0.6077
Spry drying / Andro:γCD(1:2) / 150 / 10 / 0.0535 / 0.0926 / 0.8762
Spry drying / Andro:βCD(1:2)+ a / 150 / 5 / 0.0696 / 0.1080 / 0.7388
Spry drying / Andro:βCD(1:2) + b / 150 / 5 / 0.0670 / 0.0975 / 0.7240
Spry drying / Andro:γCD(1:2) + c / 150 / 5 / 0.0616 / 0.1006 / 0.8976
Spry drying / Andro:γCD(1:1) + b / 150 / 5 / 0.0612 / 0.1101 / 0.8289
Spry drying / Andro:βCD(1:1) / 150 / 10 / 0.0835 / 0.1128 / 0.7455
Spry drying / Andro:hpβCD(1:2) / 150 / 10 / 0.0745 / 0.1129 / 0.7167
Spry drying / Andro:hpβCD(1:2) / 150 / 10 / 0.0901 / 0.0969 / 0.6834
Spry drying / Andro:γCD(1:1) / 150 / 10 / 0.0884 / 0.1114 / 0.8359

a 0.1%PMC

b 0.1%PVP

c 0.1%HPMC

Table III. Dissolution efficiency at 120 min, DE 120 of andro, andro:CDs physical mixture and their spray dried products

βCD / γCD
SGF / SIF / SGF / SIF
Andro / 38.9 / 47.9
Physical mixture
1:1 / 57.4 / 57.3 / 62.6 / 64.3
1:2 / 61.9 / 64.7 / 68.4 / 63.8
Effect of Andro:CDx ratio
1:1 / 88.6 / 89.2 / 97.3 / 98.2
1:2 / 93.7 / 96.3 / 94.6 / 98.2
Effect of inlet temperature
110 / 92.6 / 91.4 / 92.7 / 94.8
150 / 93.7 / 96.3 / 94.6 / 98.2
Effect of feed rate of solution
5 ml/min / 83.6 / 86.3 / 96.7 / 95.4
5 ml/min / 93.7 / 96.3 / 94.6 / 98.2
5 ml/min / 93.8 / 91.4 / 93.4 / 89.8
Effect of polymer
-HPMC / 97.0 / 96.5 / 96.1 / 92.5
-PVP / 101.3 / 106.1 / 99.5 / 98.2

SGF: simulated gastric fluid

SIF: simulated intestinal fluid

Table IV. The binding energies (in kcal mol-1) and the docking energies (kcal mol-1) of the conformation instances in the preliminary docking experiment.

No. / αCD1 / βCD / γCD
Binding / Docking / Binding / Docking / Binding / Docking
1 / -5.74 / -7.01 / -7.11 / -8.34 / -8.11 / -9.07
2 / -5.65 / -6.53 / -7.95 / -9.24 / -8.47 / -9.47
3 / -6.47 / -7.60 / -8.16 / -9.23 / -8.07 / -9.02
4 / -6.24 / -7.33 / 8.05 / -9.26 / -7.94 / -9.16
5 / -7.27 / -8.02 / -7.90 / -8.74 / -8.57 / -9.63
6 / -5.50 / -6.52 / -7.92 / -9.07 / -8.13 / -8.85
7 / -6.01 / -7.09 / -7.66 / -8.85 / -7.70 / -8.89
8 / -5.28 / -6.44 / -8.32 / -9.33 / -7.68 / -8.82
9 / -5.72 / -6.69 / -8.25 / -8.87 / -8.33 / -9.45
10 / -5.38 / -6.63 / -8.23 / -8.72 / -8.44 / -9.54

Table V. The bond path length (BPL, in Å), electron density (r) and Laplacian of (Ñ2r) of hydrogen bond in andro:αCD1

Normal hydrogen bond / Double hydrogen bond
HB / BPL / r / Ñ2r / HB / BPL / r / Ñ2r
In CD / in CD
O1…H108 / 2.410 / 0.012 / 0.037 / in Andro
O8…H107 / 2.130 / 0.018 / 0.051 / H152…H175 / 2.019 / 0.015 / 0.054
O15…H118 / 2.337 / 0.014 / 0.040 / H154…H173 / 2.070 / 0.012 / 0.044
O17…H117 / 2.142 / 0.017 / 0.049 / H157…H160 / 2.125 / 0.012 / 0.048
O24…H68 / 2.279 / 0.016 / 0.043 / H159…H165 / 1.966 / 0.015 / 0.048
O26…H126 / 2.192 / 0.015 / 0.044 / H161…H173 / 1.938 / 0.016 / 0.048
O28…H67 / 2.135 / 0.017 / 0.050 / H166…H174 / 2.053 / 0.014 / 0.048
O35…H78 / 2.316 / 0.015 / 0.042 / H170…H176 / 2.201 / 0.012 / 0.052
O37…H76 / 2.172 / 0.015 / 0.046 / H170…H177 / 2.483 / 0.010 / 0.040
O39…H77 / 2.116 / 0.018 / 0.052 / H172…H176 / 2.134 / 0.012 / 0.044
O46…H88 / 2.356 / 0.014 / 0.040 / Intermolecule
O48…H86 / 2.178 / 0.015 / 0.046 / H72…H157 / 2.347 / 0.005 / 0.021
O50…H87 / 2.125 / 0.017 / 0.051 / H82…H160 / 2.781 / 0.002 / 0.008
O57…H98 / 2.293 / 0.015 / 0.041 / H92…H163 / 2.328 / 0.004 / 0.016
O59…H96 / 2.187 / 0.015 / 0.044 / H112…H161 / 2.245 / 0.008 / 0.025
O61…H97 / 2.146 / 0.017 / 0.049 / H115…H173 / 2.252 / 0.007 / 0.027
O64…H106 / 2.177 / 0.015 / 0.046 / H116…H154 / 2.315 / 0.007 / 0.028
O66…H116 / 2.139 / 0.017 / 0.050 / H122…H155 / 2.379 / 0.006 / 0.026
In andro / H125…H155 / 2.486 / 0.005 / 0.021
O127…H162 / 2.306 / 0.018 / 0.063
O132…H166 / 2.595 / 0.010 / 0.041
O151…H175 / 2.633 / 0.009 / 0.034
Intermoleculea

a intermolecular hydrogen bonds, details can be found in Table 4 of the text.

Table VI. The bond path length (BPL, in Å), electron density (r) and Laplacian of (Ñ2r) of hydrogen bond in andro:αCD2

Normal hydrogen bond / Double hydrogen bond
HB / BPL / r / Ñ2r / HB / BPL / r / Ñ2r
in CD / in CD
O1…H107 / 2.646 / 0.006 / 0.026 / in andro
O8…H107 / 2.117 / 0.019 / 0.053 / H156…H160 / 2.327 / 0.010 / 0.043
O1…H108 / 2.521 / 0.010 / 0.035 / H157…H178 / 2.034 / 0.015 / 0.055
O15…H118 / 2.281 / 0.016 / 0.044 / H158…H160 / 2.202 / 0.012 / 0.051
O17…H117 / 2.147 / 0.016 / 0.049 / H158…H179 / 2.138 / 0.012 / 0.043
O24…H68 / 2.256 / 0.016 / 0.044 / H164…H172 / 1.958 / 0.015 / 0.048
O26…H126 / 2.204 / 0.014 / 0.043 / H165…H180 / 2.043 / 0.014 / 0.049
O28…H67 / 2.134 / 0.018 / 0.050 / H167…H181 / 1.903 / 0.016 / 0.046
O35…H77 / 2.776 / 0.005 / 0.023 / H171…H174 / 2.143 / 0.012 / 0.049
O35…H78 / 2.462 / 0.011 / 0.037 / H176…H181 / 2.080 / 0.012 / 0.043
O37…H76 / 2.214 / 0.013 / 0.042 / Intermolecule
O39…H77 / 2.124 / 0.018 / 0.052 / H70…H153 / 2.534 / 0.005 / 0.018
O46…H88 / 2.344 / 0.014 / 0.040 / H72…H152 / 2.448 / 0.005 / 0.020
O48…H86 / 2.202 / 0.015 / 0.043 / H82…H152 / 2.214 / 0.007 / 0.024
O50…H87 / 2.153 / 0.016 / 0.048 / H82…H152 / 2.725 / 0.005 / 0.020
O57…H98 / 2.288 / 0.016 / 0.042 / H115…H162 / 2.183 / 0.006 / 0.019
O59…H96 / 2.204 / 0.015 / 0.044 / H116…H177 / 2.239 / 0.006 / 0.023
O61…H97 / 2.152 / 0.017 / 0.048 / H120…H153 / 2.751 / 0.002 / 0.008
O64…H106 / 2.206 / 0.014 / 0.043 / H122…H154 / 2.148 / 0.008 / 0.022
O66…H116 / 2.213 / 0.014 / 0.042 / H125…H173 / 2.432 / 0.009 / 0.034
in Andro / H125…H175 / 2.220 / 0.006 / 0.025
O133…H157 / 2.584 / 0.009 / 0.034 / H125…H177 / 2.459 / 0.009 / 0.030
O150…H165 / 2.468 / 0.013 / 0.048
O151…H168 / 2.328 / 0.017 / 0.063
Intermoleculea

a intermolecular hydrogen bonds, details can be found in Table 5 of the text.

Table VII. The bond path length (BPL, in Å), electron density (r) and Laplacian of (Ñ2r) of hydrogen bond in andro:βCD1

Normal hydrogen bond / Double hydrogen bond
HB / BPL / r / Ñ2r / HB / BPL / r / Ñ2r
in CD / in CD
O26…H145 / 2.678 / 0.007 / 0.023 / H146…H147 / 7.769 / 0 / 0
O26…H170 / 2.213 / 0.015 / 0.045 / in andro
O29…H168 / 2.337 / 0.015 / 0.045 / H180…H186 / 1.992 / 0.015 / 0.047
O39…H108 / 2.223 / 0.018 / 0.048 / H182…H187 / 2.169 / 0.012 / 0.051
O43…H110 / 2.138 / 0.018 / 0.051 / H183…H194 / 1.860 / 0.017 / 0.043
O47…H118 / 2.288 / 0.016 / 0.047 / H187…H195 / 2.125 / 0.012 / 0.048
O51…H112 / 2.174 / 0.015 / 0.046 / H191…H200 / 2.375 / 0.008 / 0.027
O54…H158 / 2.314 / 0.015 / 0.04 / H193…H197 / 2.196 / 0.011 / 0.044
O60…H172 / 2.218 / 0.014 / 0.042 / H173…H196 / 2.007 / 0.016 / 0.053
O62…H160 / 2.147 / 0.018 / 0.052 / H175…H183 / 2.393 / 0.008 / 0.033
O65…H148 / 2.481 / 0.011 / 0.037 / H175…H194 / 2.241 / 0.01 / 0.04
O65…H150 / 2.647 / 0.006 / 0.027 / intermolecule
O71…H162 / 2.209 / 0.013 / 0.042 / H103…H175 / 2.665 / 0.003 / 0.011
O73…H150 / 2.204 / 0.015 / 0.044 / H103…H194 / 2.374 / 0.005 / 0.017
O76…H138 / 2.289 / 0.015 / 0.043 / H105…H175 / 2.679 / 0.003 / 0.011
O82…H152 / 2.186 / 0.015 / 0.045 / H105…H183 / 2.183 / 0.008 / 0.024
O84…H140 / 2.173 / 0.016 / 0.045 / H113…H182 / 2.382 / 0.006 / 0.02
O87…H128 / 2.301 / 0.015 / 0.041 / H113…H187 / 2.602 / 0.003 / 0.012
O93…H142 / 2.138 / 0.017 / 0.05 / H113…H195 / 2.956 / 0.002 / 0.008
O95…H128 / 2.697 / 0.007 / 0.027 / H123…H186 / 2.424 / 0.005 / 0.016
O95…H130 / 2.345 / 0.012 / 0.039 / H125…H180 / 2.193 / 0.007 / 0.023
O98…H132 / 2.169 / 0.015 / 0.047 / H125…H182 / 2.612 / 0.003 / 0.014
O100…H120 / 2.255 / 0.013 / 0.039 / H135…H180 / 2.253 / 0.01 / 0.039
O102…H122 / 2.204 / 0.014 / 0.043 / H140…H181 / 2.780 / 0.004 / 0.014
in andro / H143…H179 / 2.555 / 0.004 / 0.013
O18…H184 / 2.115 / 0.023 / 0.073 / H145…H179 / 2.555 / 0.004 / 0.014
O24…H197 / 2.484 / 0.011 / 0.035 / H153…H174 / 2.834 / 0.002 / 0.007
intermoleculea / H155…H177 / 2.142 / 0.009 / 0.032
H163…H176 / 2.059 / 0.011 / 0.033
H165…H176 / 2.319 / 0.007 / 0.026

a intermolecular hydrogen bonds, details can be found in Table 6 of the text.

Table VIII. The bond path length (BPL, in Å), electron density (r) and Laplacian of (Ñ2r) of hydrogen bond in andro:βCD2

Normal hydrogen bond / Double hydrogen bond
HB / BPL / r / Ñ2r / HB / BPL / r / Ñ2r
in CD / in CD
O4…H83 / 2.206 / 0.018 / 0.049 / in andro
O9…H143 / 2.388 / 0.013 / 0.043 / H176…H179 / 2.275 / 0.007 / 0.026
O16…H133 / 2.182 / 0.019 / 0.051 / H176…H191 / 2.634 / 0.003 / 0.013
O23…H123 / 2.336 / 0.014 / 0.039 / H177…H181 / 2.356 / 0.008 / 0.037
O30…H113 / 2.437 / 0.012 / 0.038 / H178…H192 / 2.004 / 0.016 / 0.055
O30…H115 / 2.774 / 0.005 / 0.024 / H180…H181 / 2.222 / 0.012 / 0.053
O37…H103 / 2.227 / 0.017 / 0.049 / H180…H189 / 2.172 / 0.011 / 0.044
O44…H93 / 2.250 / 0.016 / 0.044 / H185…H188 / 2.065 / 0.013 / 0.048
O51…H93 / 2.562 / 0.009 / 0.034 / H185…H199 / 2.300 / 0.009 / 0.038
O51…H95 / 2.239 / 0.015 / 0.046 / H186…H201 / 1.960 / 0.016 / 0.048
O52…H97 / 2.172 / 0.015 / 0.046 / H190…H194 / 2.094 / 0.012 / 0.043
O55…H105 / 2.165 / 0.016 / 0.046 / H190…H197 / 1.916 / 0.016 / 0.048
O56…H107 / 2.172 / 0.015 / 0.047 / H196…H202 / 2.102 / 0.012 / 0.048
O59…H115 / 2.165 / 0.016 / 0.047 / DHB intermolecule
O60…H117 / 2.175 / 0.016 / 0.047 / H78…H177 / 2.508 / 0.004 / 0.014
O63…H125 / 2.174 / 0.018 / 0.051 / H78…H181 / 2.517 / 0.010 / 0.033
O64…H127 / 2.208 / 0.014 / 0.042 / H86…H182 / 2.320 / 0.007 / 0.032
O67…H110 / 2.611 / 0.008 / 0.026 / H88…H180 / 2.106 / 0.009 / 0.026
O67…H135 / 2.351 / 0.012 / 0.037 / H90…H177 / 2.575 / 0.005 / 0.018
O68…H137 / 2.166 / 0.015 / 0.047 / H98…H175 / 2.595 / 0.005 / 0.019
O71…H145 / 2.154 / 0.017 / 0.048 / H98…H178 / 2.563 / 0.003 / 0.012
O72…H147 / 2.228 / 0.014 / 0.041 / H100…H175 / 2.258 / 0.005 / 0.018
O75…H85 / 2.190 / 0.017 / 0.048 / H110…H173 / 2.281 / 0.006 / 0.018
O76…H87 / 2.196 / 0.014 / 0.044 / H117…H193 / 4.053 / 0.000 / 0.001
in andro / H118…H174 / 2.753 / 0.003 / 0.010
O168…H198 / 2.291 / 0.018 / 0.065 / H120…H173 / 2.164 / 0.010 / 0.038
O155…H178 / 2.409 / 0.013 / 0.039 / H138…H183 / 4.369 / 0.000 / 0.000
O155…H191 / 3.048 / 0.003 / 0.014
Intermoleculea

a intermolecular hydrogen bonds, details can be found in Table 7 of the text.