Discovery of Potential M2 Channel Inhibitors Based on the Amantadine Scaffold via Virtual Screening and Pharmacophore Modeling
Abstract
:1. Introduction
2. Results and Discussion
2.1. Binding Site Identification
Position | Ligand | Binding energy (kcal/mol) | Possible binding sites with M2 channel proteins | ||
---|---|---|---|---|---|
H3N2 | 2009-H1N1 | H3N2 | 2009-H1N1 | ||
Inside | Amantadine | −6.85 | −7.01 | Hydrogen bond with Ala30 | No Hydrogen bond |
Inside | Rimantadine | −7.75 | −7.57 | Hydrogen bond with Ala30 | No Hydrogen bond |
Hydrophobic interaction with Ile33 | Hydrophobic interaction with Ile33 | ||||
Outside | Amantadine | −5.03 | −5.05 | Hydrogen bond with Asp44 | Hydrogen bond with Asp44 |
Outside | Rimantadine | −5.53 | −4.92 | Hydrogen bond with Asp44 | Hydrogen bond with Asp44 |
Hydrophobic interaction with Thr43 |
2.2. Docking Results and Ranking Top Hit Compounds Binding Inside and Outside M2 Channel Proteins
Compound No. | 2D Chemical Structure | INSIDE Free energy of binding (kcal/mol) | OUTSIDE Free energy of binding (kcal/mol) | ||
---|---|---|---|---|---|
H3N2 | 2009-H1N1 | H3N2 | 2009-H1N1 | ||
Group 1 (A1-A5) from [10] | |||||
A1 | | −6.85 | −7.02 | −5.03 | −5.05 |
A2 | | −7.75 | −7.57 | −5.53 | −4.92 |
A3 | | −8.48 | −7.69 | −5.50 | −4.36 |
A4 | | −8.09 | −7.79 | −5.25 | −4.55 |
A5 | | −8.16 | −8.40 | −4.85 | −4.89 |
Group 2 from [18] | |||||
B1 | | −6.85 | −6.55 | −5.53 | −5.51 |
B2 | | −7.10 | −6.82 | −5.81 | −5.36 |
B3 | | −7.82 | −7.57 | −5.17 | −5.02 |
B4 | | −7.44 | −7.08 | −5.65 | −5.21 |
B5 | | −7.70 | −7.42 | −5.53 | −5.20 |
B6 | | −7.97 | −7.69 | −5.52 | −5.42 |
B7 | | −8.32 | −8.67 | −6.15 | −5.40 |
B8 | | −8.53 | −8.21 | −5.78 | −5.23 |
B9 | | −8.58 | −8.23 | −6.02 | −5.04 |
B10 | | −8.93 | −9.25 | −5.81 | −5.80 |
Group 3 from [21] | |||||
1a | | −8.70 | −8.48 | −6.04 | −6.11 |
1b | | −9.46 | −8.91 | −6.49 | −5.51 |
1c | | −9.39 | −8.89 | −6.55 | −3.04 |
1d | | −9.20 | −9.62 | −4.71 | −2.60 |
1e | | −8.99 | −9.81 | −4.45 | −0.30 |
1f | | −8.73 | −8.54 | −5.45 | −5.01 |
1g | | −9.91 | −9.80 | −5.32 | −2.52 |
1h | | −9.53 | −9.07 | −4.62 | −0.15 |
1i | | −10.29 | −10.02 | −7.33 | −6.72 |
2a | | −10.47 | −10.14 | −5.79 | −3.63 |
2b | | −10.48 | −10.23 | −5.42 | −3.27 |
2c | | −10.69 | −11.23 | −3.47 | +3.03 |
2d | | −10.26 | −11.35 | −4.61 | −2.52 |
2e | | −9.97 | −11.14 | −0.34 | −1.90 |
2f | | −10.30 | −10.61 | −5.98 | −5.56 |
2g | | −11.21 | −11.48 | −6.16 | −5.60 |
3a | | −10.18 | −10.40 | −4.96 | −3.93 |
3b | | −9.17 | −10.81 | +3.01 | +4.05 |
III | | −9.96 | −9.62 | −6.72 | −7.27 |
IV | | −10.20 | −10.10 | −6.57 | −7.20 |
V | | −9.71 | −9.44 | −5.88 | −5.17 |
Group 4 from [22,23] | |||||
M1 | | −8.55 | −8.44 | −5.77 | −5.69 |
M2 | | −9.03 | −8.75 | −5.53 | −5.89 |
M3 | | −8.58 | −8.43 | −5.61 | −5.63 |
M4 | | −9.05 | −8.87 | −5.85 | −5.81 |
M5 | | −8.60 | −8.23 | −5.56 | −5.64 |
M6 | | −8.47 | −8.95 | −3.62 | −4.76 |
M7 | | −8.21 | −7.97 | −5.53 | −5.23 |
M8 | | −8.65 | −7.95 | −5.97 | −4.57 |
M9 | | −9.14 | −9.20 | −4.91 | −5.88 |
M10 | | −8.47 | −8.25 | −5.05 | −5.06 |
TaM11 | | −8.44 | −8.00 | −5.62 | −4.10 |
M12 | | −9.38 | −9.59 | −5.03 | −5.97 |
M13 | | −9.42 | −9.31 | −4.16 | −5.89 |
M14 | | −6.73 | −6.89 | −5.07 | −4.40 |
M15 | | −9.09 | −8.91 | −5.75 | −5.70 |
M16 | | −9.04 | −8.27 | −5.73 | −5.04 |
M17 | | −9.58 | −9.48 | −4.19 | −5.69 |
M18 | | −9.70 | −8.87 | −4.34 | −4.71 |
M19 | | −10.03 | −9.33 | −4.23 | −4.67 |
M20 | | −9.48 | −9.27 | −5.94 | −5.14 |
M21 | | −9.72 | −9.61 | −5.91 | −5.12 |
M22 | | −10.19 | −9.49 | −6.15 | −4.09 |
M23 | | −10.63 | −10.08 | −5.49 | −2.87 |
M24 | | −11.59 | −11.23 | −7.26 | −3.36 |
Bananin | | −9.67 | −9.39 | −3.83 | −4.40 |
Iodobananin(IBN) | | −9.60 | −10.16 | −4.96 | −5.36 |
Eubananin(EUB) | | −8.54 | −8.51 | +1.71 | +3.06 |
Vanillinbananin(VBN) | | −8.70 | −9.22 | −4.58 | −4.74 |
Group 5 from [24] | |||||
D1 | | −8.48 | −8.26 | −5.38 | −5.06 |
D2 | | −7.83 | −7.94 | −5.58 | −5.20 |
D3 | | −7.38 | −6.91 | −4.27 | −3.86 |
D4 | | −7.46 | −7.29 | −5.69 | −5.53 |
D5 | | −8.01 | −7.93 | −5.61 | −5.70 |
D6 | | −7.79 | −7.59 | −5.17 | −5.15 |
D7 | | −8.54 | −8.27 | −5.72 | −5.60 |
D8 | | −9.10 | −8.86 | −6.12 | −5.72 |
D9 | | −7.12 | −7.37 | −5.51 | −4.77 |
D10 | | −7.75 | −7.84 | −4.30 | −4.93 |
D11 | | −8.17 | −8.50 | −4.78 | −4.98 |
D12 | | −7.96 | −8.65 | −4.47 | −5.19 |
D13 | | −8.77 | −8.86 | −4.69 | −5.93 |
D14 | | −9.28 | −9.62 | −5.05 | −6.13 |
D15 | | −6.99 | −6.83 | −4.97 | −4.88 |
D16 | | −7.17 | −7.02 | −5.01 | −4.50 |
Group 6 from [25,26] | |||||
N1 | | −9.38 | −9.74 | −5.51 | −5.51 |
N2 | | −8.57 | −8.26 | −5.65 | −5.17 |
N3 | | −12.09 | −11.76 | −6.72 | −6.72 |
N4 | | −9.62 | −9.91 | −5.91 | −6.21 |
N5 | | −9.76 | −9.87 | −5.42 | −4.82 |
N6 | | −10.44 | −10.31 | −5.55 | −3.69 |
N7 | | −10.15 | −10.70 | −5.54 | −5.25 |
N8 | | −7.37 | −7.06 | −5.22 | −4.77 |
N9 | | −8.50 | −7.58 | −5.50 | −5.06 |
N10 | | −8.83 | −8.50 | −5.18 | −5.23 |
N11 | | −9.24 | −8.97 | −5.25 | −5.36 |
N12 | | −9.53 | −9.34 | −5.94 | −6.46 |
N13 | | −10.49 | −10.41 | −5.76 | −5.29 |
N14 | | −12.25 | −12.10 | −6.68 | −3.99 |
N15 | | −10.98 | −10.12 | −5.68 | −4.78 |
N16 | | −12.50 | −12.13 | −6.44 | −3.86 |
N17 | | −9.73 | −9.47 | −4.49 | −3.30 |
N18 | | −9.97 | −9.73 | −3.64 | −3.36 |
N19 | | −12.52 | −12.00 | −1.18 | +4.19 |
N20 | | −6.98 | −7.26 | −5.08 | −4.60 |
N21 | | −9.06 | −9.30 | −5.20 | −5.64 |
Group 7 | |||||
1 | | −7.50 | −7.72 | −5.16 | −5.06 |
2 | | −8.21 | −6.87 | −6.24 | −4.37 |
3 | | −8.08 | −8.18 | −5.35 | −5.27 |
4 | | −9.24 | −8.97 | −5.25 | −5.36 |
5 | | −8.41 | −7.75 | −5.21 | −4.69 |
6 | | −8.46 | −8.25 | −5.20 | −4.93 |
7 | | −7.62 | −7.45 | −5.00 | −4.42 |
8 | | −8.14 | −7.78 | −5.09 | −4.64 |
9 | | −8.85 | −8.42 | −5.27 | −5.05 |
10 | | −9.35 | −8.97 | −5.59 | −5.35 |
11 | | −9.23 | −9.51 | −6.17 | −6.96 |
12 | | −10.59 | −10.11 | −7.13 | −6.92 |
13 | | −10.51 | −10.28 | −6.73 | −7.62 |
14 | | −11.21 | −10.61 | −7.13 | −7.30 |
15 | | −10.67 | −10.46 | −6.49 | −7.68 |
16 | | −11.22 | −10.84 | −7.25 | −7.50 |
17 | | −8.04 | −8.23 | −5.36 | −5.18 |
18 | | −8.80 | −8.00 | −6.37 | −6.03 |
19 | | −9.16 | −9.47 | −6.17 | −6.95 |
20 | | −9.67 | −9.67 | −6.12 | −6.73 |
21 | | −10.00 | −10.50 | −5.99 | −5.41 |
22 | | −9.64 | −10.03 | −5.55 | −5.32 |
23 | | −10.02 | −10.79 | −5.77 | −5.71 |
24 | | −10.52 | −11.20 | −5.88 | −5.57 |
25 | | −9.30 | −9.69 | −5.52 | −5.51 |
26 | | −7.80 | −7.57 | −5.57 | −5.49 |
27 | | −9.95 | −9.93 | −6.15 | −6.61 |
28 | | −10.81 | −10.77 | −5.66 | −3.76 |
29 | | −8.95 | −9.23 | −5.31 | −6.24 |
30 | | −9.43 | −10.12 | −5.68 | −5.38 |
31 | | −10.47 | −10.53 | −6.06 | −5.32 |
32 | | −10.60 | −10.70 | −6.11 | −5.99 |
33 | | −9.51 | −9.83 | −4.80 | −5.36 |
34 | | −9.70 | −9.97 | −5.37 | −5.62 |
35 | | −10.00 | −10.23 | −5.69 | −5.71 |
37 | | −8.78 | −9.17 | −5.53 | −5.63 |
38 | | −9.45 | −8.43 | −5.86 | −5.89 |
39 | | −9.18 | −8.77 | −5.32 | −5.40 |
40 | | −8.53 | −8.13 | −5.58 | −5.25 |
41 | | −9.10 | −8.78 | −5.55 | −5.56 |
42 | | −9.61 | −9.25 | −5.71 | −5.73 |
43 | | −9.42 | −9.01 | −5.26 | −5.04 |
44 | | −9.07 | −9.14 | −5.01 | −5.55 |
45 | | −9.51 | −9.55 | −3.97 | −5.73 |
46 | | −9.63 | −9.81 | −3.46 | −5.69 |
47 | | −9.90 | −10.25 | −3.53 | −5.59 |
48 | | −9.01 | −8.66 | −5.96 | −5.91 |
49 | | −9.25 | −9.21 | −5.46 | −5.55 |
50 | | −9.85 | −9.61 | −5.15 | −5.04 |
51 | | −10.11 | −9.83 | −4.14 | −4.91 |
52 | | −10.41 | −10.86 | −4.17 | −4.56 |
53 | | −11.35 | −11.97 | −5.26 | −3.29 |
54 | | −9.15 | −8.86 | −5.69 | −5.19 |
55 | | −9.55 | −9.34 | −5.37 | −5.06 |
56 | | −9.60 | −9.59 | −5.39 | −4.77 |
57 | | −9.85 | −9.70 | −5.45 | −4.42 |
58 | | −10.10 | −10.01 | −5.00 | −4.37 |
59 | | −10.74 | −10.33 | −4.91 | −5.01 |
60 | | −10.76 | −11.31 | −5.47 | −3.82 |
61 | | −9.14 | −9.23 | −4.59 | −5.69 |
62 | | −9.50 | −9.15 | −4.04 | −5.33 |
63 | | −9.88 | −9.55 | −3.69 | −4.42 |
64 | | −10.15 | −10.49 | −3.49 | −3.72 |
65 | | −9.03 | −8.74 | −5.55 | −5.90 |
66 | | −9.46 | −9.27 | −4.12 | −5.28 |
67 | | −10.06 | −9.72 | −4.47 | −3.54 |
68 | | −9.92 | −9.78 | −4.13 | −5.56 |
69 | | −10.31 | −10.19 | −3.75 | −4.61 |
70 | | −10.62 | −10.38 | −3.57 | −4.70 |
71 | | −8.30 | −7.81 | −5.66 | −5.55 |
72 | | −8.60 | −8.11 | −4.77 | −4.77 |
73 | | −8.84 | −8.76 | −4.35 | −4.26 |
74 | | −9.25 | −9.04 | −3.86 | −3.89 |
75 | | −9.62 | −9.25 | −4.39 | −3.78 |
76 | | −9.80 | −9.45 | −4.07 | −3.80 |
77 | | −10.10 | −9.82 | −3.95 | −1.91 |
78 | | −10.90 | −10.95 | −4.60 | −4.48 |
79 | | −7.44 | −7.08 | −5.08 | −4.83 |
80 | | −7.87 | −7.66 | −4.93 | −4.56 |
81 | | −7.98 | −7.92 | −4.38 | −4.91 |
82 | | −8.29 | −8.11 | −4.34 | −4.59 |
83 | | −8.76 | −8.61 | −4.56 | −4.41 |
84 | | −9.01 | −8.82 | −4.65 | −4.30 |
85 | | −9.35 | −8.77 | −4.66 | −4.21 |
86 | | −10.19 | −10.15 | −5.37 | −5.29 |
87 | | −7.91 | −7.15 | −6.62 | −5.94 |
88 | | −6.94 | −6.63 | −5.34 | −4.58 |
89 | | −7.23 | −6.82 | −5.37 | −4.59 |
90 | | −9.23 | −9.04 | −6.38 | −5.84 |
91 | | −7.16 | −7.02 | −5.26 | −5.16 |
92 | | −7.40 | −7.65 | −5.69 | −5.22 |
93 | | −7.41 | −7.01 | −5.45 | −4.74 |
94 | | −7.67 | −7.39 | −5.57 | −4.91 |
95 | | −8.86 | −9.15 | −5.65 | −5.72 |
96 | | −8.00 | −7.62 | −5.23 | −4.88 |
97 | | −8.66 | −8.92 | −5.16 | −5.90 |
98 | | −8.90 | −9.01 | −5.06 | −6.16 |
99 | | −9.37 | −9.51 | −5.20 | −6.42 |
100 | | −9.74 | −9.81 | −5.39 | −6.50 |
Inside Ranking Comp. | Top 10 binding compounds (inside M2 channel protein) | Free energy of binding (kcal/mol) | Outside Ranking Comp. | Top 10 binding compounds(outside M2 channel protein) | Free energy of binding (kcal/mol) | |||
---|---|---|---|---|---|---|---|---|
H3N2 | 2009-H1N1 | H3N2 | 2009-H1N1 | |||||
I1 | | −12.50 | −12.13 | O1 | | −6.49 | −7.68 | |
I2 | | −12.25 | −12.10 | O2 | | −6.73 | −7.62 | |
I3 | | −12.52 | −12.00 | O3 | | −7.25 | −7.50 | |
I4 | | −11.35 | −11.97 | O4 | | −7.13 | −7.30 | |
I5 | | −12.09 | −11.76 | O5 | | −6.72 | −7.27 | |
I6 | | −10.76 | −11.31 | O6 | | −6.57 | −7.20 | |
I7 | | −11.59 | −11.23 | O7 | | −6.17 | −6.96 | |
I8 | | −10.90 | −10.95 | O8 | | −7.13 | −6.92 | |
I9 | | −11.22 | −10.84 | O9 | | −6.72 | −6.72 | |
I10 | | −10.81 | −10.77 | O10 | | −7.33 | −6.72 |
2.3. Pharmacophore Analysis for Top hits M2 Channel-Inhibitor Interactions
Cartoon Representation of M2 protein complex | Protein-Ligand Interactions | Hypothesis |
---|---|---|
I5 inside M2 channel | ||
| | |
I9 inside M2 channel | ||
| | |
I5 outside M2 channel | ||
| | |
I9 outside M2 channel | ||
| | |
2.4. Common Pharmacophore Features of the Top Binding Compounds
3. Experimental
3.1. Proteins and Inhibitor Preparation
3.2. Virtual Screening with Autodock 3.05
3.3. Pharmacophore Modeling
3.3.1. Generation of Structure-Based Pharmacophore Models Using LigandScout 3.01
3.3.2. Ligand-Based Pharmacophore Modeling Using Discovery Studio 2.5
4. Conclusions
Acknowledgments
References and Notes
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Tran, L.; Choi, S.B.; Al-Najjar, B.O.; Yusuf, M.; Wahab, H.A.; Le, L. Discovery of Potential M2 Channel Inhibitors Based on the Amantadine Scaffold via Virtual Screening and Pharmacophore Modeling. Molecules 2011, 16, 10227-10255. https://doi.org/10.3390/molecules161210227
Tran L, Choi SB, Al-Najjar BO, Yusuf M, Wahab HA, Le L. Discovery of Potential M2 Channel Inhibitors Based on the Amantadine Scaffold via Virtual Screening and Pharmacophore Modeling. Molecules. 2011; 16(12):10227-10255. https://doi.org/10.3390/molecules161210227
Chicago/Turabian StyleTran, Linh, Sy Bing Choi, Belal O. Al-Najjar, Muhammad Yusuf, Habibah A. Wahab, and Ly Le. 2011. "Discovery of Potential M2 Channel Inhibitors Based on the Amantadine Scaffold via Virtual Screening and Pharmacophore Modeling" Molecules 16, no. 12: 10227-10255. https://doi.org/10.3390/molecules161210227