Figure 1: Redock alignment CHIKV macrodomain with ligand ADP ribose - substrate - in sticks (left) and SARS-Cov2 macrodomain (right)
Table 1: Docking studies with CHIKV nsp3 Macrodomain
Table 2: Molecular Dynamic studies with CHIKV nsp3 Macrodomain
Table 3: Virtual Hits obtained in nsp3 macrodomain docking studies
Table 4: Frequency of identified h-bond in the Clustered complex along the 100ns of simulation
Author-compound name |
EC50 |
IC50 |
CC50 |
SI |
proposed target |
Abdelnabi16-1 |
4.3 ±0.5 |
|
>50 |
>11.62 |
PKCs |
Abdelnabi16-2 |
8 |
|
>50 |
>6,25 |
PKC independent via |
Abdelnabi16-3 |
7.2 |
|
>50 |
>6.94 |
PKC independent via |
Abdelnabi17-Prostatin |
0.2 |
|
>50 |
|
PKCs |
Aggarwal17-Piperazine |
? |
|
? |
|
virus assembly and |
Ashbrook16-digoxin |
0.0488 |
|
? |
|
after entry\Na+ K+ |
Ashbrook16-ouabain |
? |
|
? |
|
after entry\Na+ K+ |
Bassetto13-1 |
5 ±0.2 |
|
72 ±20 |
14 |
nsp2 docking |
Bassetto13-13 |
5.6 ±2.0 |
|
72 ±2 |
13 |
nsp2 docking |
Bassetto13-2 |
4 ±0.3 |
|
20 ±2 |
5 |
nsp2 docking |
Bassetto13-25 |
3.2 ±1.8 |
|
101 ±50 |
32 |
nsp2 docking |
Bassetto13-8 |
3.6 ±0.9 |
|
6.1 ±2.3 |
1.7 |
nsp2 docking |
Bourjot12-prostatin (2) |
2.6 |
|
79 ±17.4 |
30.3 |
PKCs |
Bourjot12-TPA (4) |
0.0029 |
|
5.7 ±1.7 |
1965 |
PKCs |
Bourjot14-trigocherrierin A |
0.6 ±0.1 |
|
43 ±16 |
71.7 |
?? |
Ching15-15c |
2 |
|
>100 |
>50 |
|
Ching17-20 |
3 |
|
>100 |
33.33 |
Late replication events |
Ching17-23c |
7 |
|
>100 |
14.28 |
Late replication events |
Cruz13-CND0335 |
3.3 |
|
>50 |
>15 |
nsp2 docking |
Cruz13-CND0364 |
6.2 |
|
>50 |
>8.1 |
nsp2 docking |
Cruz13-CND0366 |
7.1 |
|
>50 |
>7 |
nsp2 docking |
Cruz13-CND0415 |
6.2 |
|
>50 |
>8.1 |
nsp2 docking |
Cruz13-CND0545 |
5.6 |
|
>50 |
>8.9 |
nsp2 docking |
Cruz13-CND3514 |
2.2 |
|
>50 |
>22.7 |
nsp2 docking |
Das16-8 |
1.5 |
|
>200 |
>133.3 |
nsp2 in vitro |
Delogu11-arbidol |
- |
12.2 |
376 |
36 |
entry/adsorption |
DiMola14-IIIe |
30 ±4 |
|
397 ±24 |
13.2 |
?? |
DiMola14-IIIf |
32 ±1.1 |
|
>468 |
14.6 |
?? |
Ehteshamia17-NHC |
1.8 ±0.2 |
|
7.7** |
|
?? |
Esposito16-14 |
15 ±3.8 |
|
36 |
2.4 |
?? |
Esposito16-7 |
5.5 ±1.7 |
|
17.6 |
3.2 |
?? |
Esposito17-10 |
4 ±0.3 |
|
42.4 |
10.6 |
?? |
Feibelman18-lobaricacid |
8.9 ±1.3 |
|
53.8 ±8.1 |
6 |
nsp1 in vitro |
Ferreira18-Sofosbuvir |
2.7 ±0.5 |
|
402 ±32 |
149 |
nsp4 docking |
Franco18-Favipiravir |
127.3 |
|
>6365 |
50 |
?? |
Franco18-Interferon-alfa(2B) |
?? |
|
|
|
?? |
Franco18-Ribavirin |
10.54 |
|
48.93 |
4.64 |
?? |
Giancotti18-41 |
5.9 ±1.1 |
|
109 |
18 |
nsp2 docking |
Giancotti18-44 |
4.3 ±0.5 |
|
52.9 |
|
nsp2 docking |
Giancotti18-51 |
11.6 |
|
nd |
- |
nsp2 docking |
Giancotti18-59 |
9.1 |
|
nd |
- |
nsp2 docking |
Giancotti18-71 |
29 |
|
nd |
- |
nsp2 docking |
Giancotti18-78 |
17.2 |
|
nd |
- |
nsp2 docking |
Giancotti18-89 |
17.9 |
|
nd |
- |
nsp2 docking |
Gigante14-15b |
3 ±1 |
|
>668 |
>222 |
?? |
Gigante17-18b |
12 ±1 |
|
>729 |
>60.75 |
nsp1 in vitro |
Gigante17-18f |
6.9 ±2 |
|
95 ±40 |
13.76 |
nsp1 in vitro |
Gigante17-8 |
3.6 ±1.3 |
|
101 ±73 |
28.05 |
nsp1 in vitro |
GómezCalderón17-Coumarin A |
26.4 |
|
7788 |
295.2 |
?? |
GómezCalderón17-Coumarin B |
1.34 |
|
1476 |
1021 |
?? |
GómezSanJuan18-15e |
1 ±0.4 |
|
>220 |
>220 |
nsp1 suggested** |
GómezSanJuan18-9b |
0.3 |
|
>220 |
>733 |
nsp1 suggested** |
Gupta14-3-methoxydebromoaplysi |
2.7 |
|
24.8 |
9.2 |
after entry |
Gupta14-debromoaplysiatoxin (2) |
1.3 |
|
13.9 |
10.9 |
after entry |
Henß16-suramin (ver albu..15) |
- |
5.68 |
162.6 |
28.6 |
entry inhibitor |
Henss18-silvestrol |
0.00189 |
|
? |
|
Host helicase eIF4A |
Hourani12-ID1452-2 |
- |
31 |
|
|
nsp2 suggested**(Bhat) |
Hwang18-SR9009 |
?? |
|
?? |
|
Late replication event |
Hwang19-Halofuginone |
?? |
|
?? |
|
?? |
Hwu15-10a |
19.1 |
|
178 |
9.3 |
?? |
Hwu15-10b |
10.2 |
|
117 |
11.5 |
?? |
Hwu15-10e |
17.2 |
|
144 |
8.8 |
?? |
Hwu15-12e |
19 |
|
107 |
5.6 |
?? |
Hwu15-14e |
13 |
|
75.2 |
5.8 |
?? |
Hwu17-2f |
2.7 ±1.2 |
|
>200 |
>74.9 |
?? |
Hwu17-2g |
2 ±1.2 |
|
>200 |
>100 |
?? |
Hwu17-2j |
1.6* |
|
50 |
<32* |
?? |
Hwu17-3f |
1.9 ±1.2 |
|
>200 |
>100 |
?? |
Hwu17-3g |
1.5* |
|
>200 |
<133* |
?? |
Hwu17-3i |
2.3 ±1.3 |
|
>200 |
>87 |
?? |
Hwu19-14k |
13.9 |
|
>227 |
>16.3 |
?? |
Hwu19-7f |
9.9 |
|
>212 |
>21.7 |
?? |
Hwu19-7g |
10.3 |
|
96.5 |
9.37 |
?? |
Jadav14-16 |
- |
40.1 |
>100 |
>2.49 |
nsp2 docking |
Jadav14-19 |
- |
6.8 |
>100 |
>14.7 |
nsp2 docking |
Jadav14-7 |
- |
0.42 |
>100 |
>238 |
nsp2 docking |
Jadav14-8 |
- |
4.2 |
>100 |
>23.8 |
nsp2 docking |
Jadav14-9 |
- |
3.6 |
>100 |
>27.7 |
nsp2 docking |
Kaur12-harringtonine |
0.24 |
|
?? |
|
early and late replication |
Lani15-silymarin |
- |
35 |
633.03 |
18.08 |
after entry |
Lani16-baicalein |
- |
6.99 |
1755 |
251 |
early replication event |
Lani16-fisetin |
- |
29.5 |
741 |
25.11 |
early replication event |
Lani16-quercetagetin |
- |
43.52 |
164 |
3.76 |
early replication event |
Lin17-nobiletin |
68.7 |
|
? |
? |
?? |
Mishra16-MBZM-N-IBT |
38.68 |
|
>800 |
20.68 |
?? |
Mounce17-Bisdemethoxy-cucurmin |
4.84 |
|
16 |
3.30 |
?? |
Mounce17-Cucurmin |
3.89 |
|
11.6 |
2.98 |
Cell binding inhibition |
Mounce17-Demethoxy-cucurmin |
0.89 |
|
13.2 |
14.83 |
membrana... |
Murali15-apigenin |
- |
Extract |
|
|
after entry |
Murali15-luteolin |
- |
Extract |
|
|
after entry |
NothiasScaglia14-3 |
0.76 ±14 |
|
159 |
208 |
PKCs |
NothiasScaglia15-10 |
3.2 |
|
5.76 |
1.8 |
PKCs |
NothiasScaglia15-11 |
0.006 |
|
4.1 |
686 |
PKCs |
NothiasScaglia15-12 |
1.5 |
|
3.3 |
2.2 |
PKCs |
NothiasScaglia15-13 |
0.0029 |
|
5.7 |
1965 |
PKCs |
NothiasScaglia15-14 |
2.8 |
|
5.32 |
1.9 |
PKCs |
NothiasScaglia15-15 |
1.1 |
|
3.63 |
3.3 |
PKCs |
NothiasScaglia15-18 |
0.6 |
|
2.22 |
3.7 |
PKCs |
NothiasScaglia15-19 |
1.7 |
|
24.14 |
14.2 |
PKCs |
NothiasScaglia15-22 |
0.7 |
|
4.13 |
5.9 |
PKCs |
NothiasScaglia15-23 |
2.7 |
|
61.56 |
22.8 |
PKCs |
NothiasScaglia15-24 |
0.7 |
|
3.5 |
5 |
PKCs |
NothiasScaglia15-28 |
1.2 |
|
7.68 |
6.4 |
PKCs |
NothiasScaglia15-29 |
1.8 |
|
4.14 |
2.3 |
PKCs |
NothiasScaglia15-3 |
4.9 |
|
7.35 |
1.5 |
PKCs |
NothiasScaglia15-6 |
2.2 |
|
21.34 |
9.7 |
PKCs |
NothiasScaglia15-7 |
0.99 |
|
8.91 |
9 |
PKCs |
NothiasScaglia15-8 |
9.4 |
|
39.48 |
4.2 |
PKCs |
NothiasScaglia15-9 |
1.8 |
|
3.78 |
2.1 |
PKCs |
Pryke17-AV-C |
? |
|
|
|
transcription and |
Scuotto16-IIc |
6.5 ±1 |
|
156 |
22 |
?? |
Sharma18-Miltefosine |
8.1 ??? |
|
?? |
|
Akt- phosphorylation |
Singh18-pepI |
- |
34 |
5 |
0.14 |
nsp2 in vitro Ki 33uM |
Singh18-pepII |
- |
42 |
>300 |
>7.14 |
nsp2 in vitro Ki 45uM |
Staveness16-bryo-10 |
4 |
|
>50 |
>12.5 |
PKC independent via |
Staveness16-bryo-11 |
3.7 |
|
41 |
11.08 |
PKC independent via |
Staveness16-bryo-14 |
3.4 |
|
>50 |
>14.70 |
PKC independent via |
Staveness16-bryo-16 |
2.2 |
|
>50 |
>22.72 |
PKC independent via |
Staveness16-bryo-17 |
3.1 |
|
>50 |
>16.12 |
PKC independent via |
Staveness16-bryo-4 |
3.7 |
|
>50 |
>13.51 |
PKC independent via |
Staveness16-bryo-5 |
2 |
|
>50 |
>25 |
PKC independent via |
Staveness16-bryo-6 |
1.4 |
|
>50 |
>35.71 |
PKC independent via |
Staveness16-bryo-7 |
2.8 |
|
>50 |
>17.85 |
PKC independent via |
Staveness16-bryo-8 |
2 |
|
>50 |
>25 |
PKC independent via |
Staveness16-bryo-9 |
3.5 |
|
>50 |
>14.28 |
PKC independent via |
Tardugno18-11a |
5.9 ±0.8 |
|
117 |
19.8 |
nsp2 docking |
Tardugno18-12a |
5.8 ±0.9 |
|
124 ±7.1 |
21.4 |
nsp2 docking |
Varghese16-abamectin |
1.5 |
|
28.2 |
19.2 |
early and late replication |
Varghese16-berberine |
35.3 |
|
800 |
22.66 |
MAPK signaling |
Varghese16-ivermectin |
0.6 |
|
37.9 |
62.4 |
early and late replication |
VonRhein16-AKBA |
6.75 |
|
>30 |
>4.44 |
?? |
VonRhein16-curcumin |
10.79 |
|
>60 |
>5.56 |
?? |
Wada17-A |
0.54 |
|
3.7 ±0.3 |
6.85 |
nsp4 -by reverse |
Wang16-niclosamide |
0.95 |
|
>20 |
21.05 |
entry inhibitor/ |
Wang16-niflumic acid |
? |
|
? |
|
entry inhibitor/ |
Wang16-nitazoxanide |
2.96 |
|
25 |
8.45 |
entry inhibitor/ |
Wang16-tolfenamic acid |
? |
|
? |
|
entry inhibitor/ |
Weber15-EGCG |
- |
12 |
* |
* |
entry inhibitor |
Wichit17-Imipramine |
? |
|
? |
|
Cholesterol Trafficking |
Wintachai15-andrographolide |
88 |
|
? |
? |
entry inhibitor |
Wintachai15-FL23 |
- |
? |
0.09 |
|
entry inhibitor |
Wintachai15-FL3 |
- |
0.02 |
0.12 |
6 |
entry inhibitor |
Wintachai15-sulfonylamidine 1m |
- |
? |
0.14 |
|
entry inhibitor |
Supplementary Table 1: Selected compounds in subset “anti-chikv” with inhibitory activity against CHIKV infected cells
The non-interacting residues were kept hidden. Symbols in table: y = hydrophobic interactions; h = H-bonds; s = salt-bridges;a = aromatic interactions; hal = halogen interactions.
Supplementary Table 2: Interacting residues from the 5 top scored molecules by subset in CHIKV macrodomain
Figure 1: Redock alignment CHIKV macrodomain with ligand ADP ribose - substrate - in sticks (left) and SARS-Cov2 macrodomain (right)
Figure 2: Up - ADPr site 2D representation with ligand at the center of picture, surrounded with interacting (labed) residues by PoseView in ProteinPlus server. Left: ADPr-macrodomain (CHIKV); Right ADPr-macrodomain (SARS-Cov2)/ Down - Sequence alignment of CHIKV and SARS-Cov2 nsp3 using structural information
Sharma18-Miltefosine (in CHIKV macrodomain)
Henß16-Suramin (in CHIKV macrodomain)
Molecular Dynamics (MD)
Figure 3: 2D protein-ligand interaction profile representation of top scored molecules from docking calculations.
Figure 4: RMSD (root mean square deviation) trajectory of receptor heavy chain atoms in 100ns Molecular Dynamics simulation
Figure 5: RMSF (root mean square fluctuation) trajectory of receptor heavy chain atoms in 100ns Molecular Dynamics simulation
Figure 6: Left: Hydrophobic surface representation of NothiasScaglia15-18 in the receptor binding pocket (by Chimera). Right: The interacting residues (by PLIP).
Tables at a glance
Figures at a glance