The H+/K+-ATPase or proton pump is a magnesium-dependant enzyme which causes the exchange of a proton against a potassium ion through a membrane. Over activity of this enzyme causes hyperacidity by producing more of hydrochloric acid inside the stomach. This enzyme, therefore, has been found to be a good target for designing compounds to treat hyperacidity. A quantitative structure-activity relationship (QSAR) study has been made on a novel series of biaryl imidazole derivatives acting as H+/K+-ATPase inhibitors. The H+/K+-ATPase inhibition activity of these compounds is found to be significantly correlated with global topological charge indices (GTCIs) and the total polar surface area (TPSA) of the molecules, indicating the involvement of strong electronic interaction between the molecule and the receptor. Based on the correlations obtained, some new H+/K+-ATPase inhibitors are predicted. The docking studies of these predicted compounds exhibit that these compounds will have even better interaction with the receptor than those already marketed. Thus, they can prove more potent drugs for the treatment of hyperacidity.
The hyperactivity of H+/K+-ATPase, the enzyme located in the parietal cells, is responsible for the final step of acid secretion in the stomach, leading to many acid-related diseases, such as stomach and duodenal ulcers, symptoms of esophagitis (inflammation of esophagus, the tube from the mouth to the stomach), and severe gastroesophageal reflux disease (GERD), a condition where acid leaks up from the stomach into the esophagus. This enzyme is also called proton pump. Since it is unique to parietal cells, it is considered to be a good target for developing the drugs for curing acid-related diseases [
Licensed compounds available in the market.
The quantitative structure-activity relationship (QSAR) and molecular modeling studies have been increasingly employed in rational drug discovery process to understand the drug receptor interaction and to design new molecules with higher potency. Some important QSAR studies on PPIs have been reported in the past. Ojha and coworkers [
We have taken a series of forty-two molecules of biaryl imidazoles acting as H+/K+-ATPase inhibitors that were synthesized and evaluated for their antisecretory activity by Garton et al. [
A series of H+/K+-ATPase inhibitors and their activity.
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S. no. | R | GTCI | TPSA |
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log (1/IC50) | ||
Obsda | Calcd, ( |
Pred (LOO) | ||||||
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1 | Et | 0.50 | 72.42 | 1.00 | 0.00 | 7.00 | 7.04 | 7.06 |
2 | Me | 0.52 | 72.42 | 1.00 | 0.00 | 7.10 | 7.11 | 7.10 |
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S. no. | X | Ar1 | GTCI | TPSA |
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log (1/IC50) | ||
Obsda | Calcd, ( |
Pred (LOO) | |||||||
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3 | — | Ph | 0.40 | 28.68 | 0.00 | 0.00 | 4.70 | 4.68 | 4.67 |
4 | — | 2-Me-Ph | 0.45 | 28.68 | 0.00 | 0.00 | 5.10 | 4.83 | 4.80 |
5 | — | 2,6-diMe-Ph | 0.48 | 28.68 | 0.00 | 0.00 | 5.20 | 4.95 | 4.91 |
6 | — | 2,6-diEt-Ph | 0.44 | 28.68 | 0.00 | 0.00 | 5.10 | 4.82 | 4.78 |
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— | 3-Me-triophene-4-yl | 0.45 | 28.68 | 0.00 | 0.00 | 4.80 | 4.85 | — |
8 | NH | 2,6-diMe-Ph | 0.48 | 40.71 | 0.00 | 1.00 | 4.90 | 4.53 | 4.4 |
9 | (trans) CH=CH | Ph | 0.38 | 28.68 | 0.00 | 1.00 | 4.40 | 4.03 | 3.87 |
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CH2CH2 | Ph | 0.38 | 28.68 | 0.00 | 1.00 | 4.30 | 4.03 | — |
11 | NHC0H2 | 2,6-diMe-Ph | 0.47 | 40.71 | 0.00 | 1.00 | 4.30 | 4.57 | 4.55b |
12 | CONH | Ph | 0.42 | 57.78 | 0.00 | 1.00 | 4.00 | 4.58 | 4.72 |
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Ortho | Ph | 0.38 | 28.68 | 0.00 | 1.00 | 4.20 | 4.00 | 4.17 |
14 | Para | 2,6-diMe-Ph | 0.50 | 28.68 | 0.00 | 1.00 | 4.40 | 4.40 | 4.43 |
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S. no. | X | Y | R1 | R2 | R3 | GTCI | TPSA |
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log (1/IC50) | ||
Obsda | Calcd, ( |
Pred (LOO) | ||||||||||
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N | C | H | H | H | 0.36 | 28.68 | 0.00 | 0.00 | 4.50 | 4.53 | — |
16 | N | C | H | Et | Et | 0.45 | 26.68 | 0.00 | 0.00 | 4.80 | 4.80 | 4.80 |
17 | N | C | H | Ph | — | 0.36 | 28.68 | 0.00 | 0.00 | 4.40 | 4.52 | 5.32 |
18c | N | C | Me | H | H | 0.41 | 17.82 | 0.00 | 0.00 | 5.20 | 4.54 | — |
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N | C | Me | Me | Me | 0.49 | 17.82 | 0.00 | 0.00 | 4.60 | 4.83 | — |
20 | N | C | N-Pr | H | H | 0.39 | 17.82 | 0.00 | 0.00 | 4.30 | 4.46 | 4.48 |
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CH | N | — | Me | Me | 0.48 | 17.82 | 0.00 | 0.00 | 4.80 | 4.80 | — |
22 | CH | N | n-Pr | H | — | 0.41 | 17.82 | 0.00 | 0.00 | 4.40 | 4.54 | 4.55 |
23 | — | — | — | — | — | 0.42 | 38.91 | 0.00 | 0.00 | 4.50 | 4.86 | 4.88 |
24 | — | — | — | — | — | 0.43 | 6.48 | 0.00 | 0.00 | 4.40 | 4.46 | 4.47 |
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— | — | — | — | — | 0.42 | 12.03 | 0.00 | 0.00 | 4.30 | 4.50 | — |
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S. no. | R | GTCI | TPSA |
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log (1/IC50) | ||
Obsda | Calcd, ( |
Pred (LOO) | ||||||
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26c | 6-OMe | 0.50 | 37.91 | 0.00 | 0.00 | 6.10 | 5.15 | — |
27 | 4-OMe | 0.50 | 37.91 | 0.00 | 0.00 | 4.90 | 5.14 | 5.12 |
28 | 4-Me | 0.51 | 26.68 | 0.00 | 0.00 | 4.90 | 5.04 | 5.04 |
29c | 5,6-DiMeO | 0.50 | 69.14 | 0.00 | 0.00 | 4.60 | 5.59 | — |
30 | 6-OH | 0.52 | 48.91 | 0.00 | 0.00 | 5.70 | 5.37 | 5.28 |
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6-OEt | 0.48 | 37.91 | 0.00 | 0.00 | 5.60 | 5.09 | — |
32 | 6-OBn | 0.42 | 37.91 | 0.00 | 0.00 | 5.30 | 4.87 | 4.81 |
33 | 6-OBn | 0.52 | 37.91 | 0.00 | 0.00 | 5.00 | 5.20 | 5.20 |
34 | 6OCH2CO2Me | 0.49 | 64.21 | 0.00 | 0.00 | 5.90 | 5.48 | 5.35 |
35 | 6OCH2CONH2 | 0.49 | 90.82 | 0.00 | 0.00 | 5.70 | 5.85 | 5.88 |
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— | 0.46 | 37.91 | 0.00 | 0.00 | 5.50 | 5.01 | — |
37 | — | 0.46 | 41.82 | 0.00 | 0.00 | 5.40 | 5.07 | 5.02 |
38 | 6-OMe-pyrid-5-yl | 0.42 | 50.80 | 0.00 | 0.00 | 4.80 | 5.05 | 5.04 |
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— | 0.48 | 27.05 | 0.00 | 0.00 | 4.90 | 4.91 | — |
40 | 2,5-Furanyl | 0.50 | 41.82 | 0.00 | 0.00 | 4.90 | 5.20 | 5.23 |
41c | 2,5-Thienyl | 0.50 | 28.68 | 0.00 | 0.00 | 4.10 | 5.02 | — |
42 | 2,4-Thienyl | 0.50 | 28.68 | 0.00 | 0.00 | 4.50 | 5.02 | 5.05 |
aTaken from [
For performing docking studies and to check the interactions between the predicted compounds, the protein has been taken from protein data bank (PDB id 2XZB), and the Mole Grow Virtual Docker software has been used for docking. The ADME/T properties are predicted with the help of Abbreviated Profile of Drugs (APOD) [
All the compounds of Table
The positive coefficient of indicator parameter
The correlation expressed by (
A plot between observed and predicted H+/K+-ATPase inhibition activities for compounds of Table
It is also to be noted that all the four parameters of (
However, certain compounds as marked with superscript “
In (
Some proposed compounds belonging to the series of Table
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No. | R | X | GTCI | TPSA |
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log (1/IC50) |
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1 |
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O | 0.519 | 81.65 | 1 | 0 | 7.24 |
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2 |
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O | 0.514 | 119.48 | 1 | 0 | 7.76 |
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3 |
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CH2 | 0.514 | 110.25 | 1 | 0 | 7.63 |
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4 |
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CH2 | 0.514 | 133.41 | 1 | 0 | 7.95 |
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5 |
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CH2 | 0.519 | 127.32 | 1 | 0 | 7.88 |
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6 |
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CH2 | 0.517 | 138.90 | 1 | 0 | 8.33 |
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7 |
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O | 0.519 | 159.71 | 1 | 0 | 8.34 |
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8 |
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O | 0.514 | 142.64 | 1 | 0 | 8.08 |
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9 |
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O | 0.514 | 131.06 | 1 | 0 | 7.92 |
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10 |
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CH2 | 0.514 | 121.83 | 1 | 0 | 7.79 |
All the compounds were docked in the protein molecule (PDB id 2XZB)using Mole Grow Virtual Docker. The docked results are cited in Table
Docking results of predicted compounds with reference to the active drugs available in the market (last four in the table).
Compound | Total interaction energy | H-bond energy | No of H-bonds | H-bonds | H-bond length (Å) | Mole dock score | Internal energy of pose |
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1 | −114.75 | −3.75 | 2 | N(22)–Glu(160) |
3.04 |
−114.75 | 6.90 |
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2 | −146.88 | −6.80 | 4 | O(26)–Gln(104) |
3.11 |
−147.54 | −0.66 |
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3 | −136.16 | −7.11 | 4 | O(29)–Gln(110) |
2.90 |
−148.35 | −12.19 |
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4 | −159.54 | −2.15 | 1 | N(29)–Gly(153) | 2.56 | −162.44 | −2.90 |
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5 | −153.23 | −8.40 | 4 | O(27)–Gln(110) |
3.16 |
−151.06 | −2.17 |
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6 | −138.98 | −6.91 | 4 | O(27)–Gly(156) |
2.35 |
−159.46 | −20.48 |
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7 | −146.85 | −7.71 | 2 | O(27)–Thr(350) |
2.62 |
−156.76 | −9.91 |
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8 | −159.24 | −5.35 | 1 | N(29)–Gly(153) | 2.60 | −146.34 | 12.90 |
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9 | −156.08 | −8.02 | 2 | O(12)–Gly(156) |
3.56 |
−147.62 | 8.48 |
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10 | −133.55 | −7.23 | 2 | O(26)–Gln(104) |
3.07 |
−144.96 | −11.41 |
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Omeprazole | −117.83 | −2.42 | 2 | O(24)–Arg(103) |
2.75 |
−111.99 | 5.84 |
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Lansoprazole | −121.59 | −0.10 | 2 | O(19)–Gly(156) |
3.48 |
−115.07 | 6.521 |
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Rabeprazole | −144.85 | −5.00 | 2 | O(11)–Thr(350) |
2.63 |
−131.76 | 13.09 |
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Pantoprazole | −120.43 | −3.78 | 3 | O(21)–Thr(350) |
3.22 |
−115.41 | 5.02 |
Data related to Lipinski rules. The last four compounds are licensed compounds given for comparision.
Predicted Compound in Table |
Lipinski Parameters | |||
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MW | HA | HD | log |
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1 | 324.377 | 5 | 2 | 2.51 |
2 | 413.467 | 8 | 5 | 0.84 |
3 | 411.494 | 7 | 5 | 0.49 |
4 | 407.555 | 7 | 5 | 0.07 |
5 | 439.504 | 8 | 5 | 0.24 |
6 | 437.534 | 8 | 5 | 0.03 |
7 | 437.538 | 9 | 5 | 0.16 |
8 | 409.527 | 8 | 5 | 0.41 |
9 | 411.497 | 8 | 5 | 0.63 |
10 | 409.525 | 7 | 5 | 0.28 |
Omeprazole | 383.370 | 8 | 1 | 2.18 |
Lansoprazole | 369.361 | 7 | 1 | 3.03 |
Rabeprazole | 339.388 | 5 | 1 | 2.56 |
Pantoprazole | 345.416 | 5 | 1 | 2.43 |
A model showing hydrogen bond interactions of predicted compound 5 (Table
The model showing hydrophobic interactions of predicted compound 5 (Table
The QSAR study on a set of biaryl imidazole derivatives performed by us has suggested that the drug-receptor interaction involves the strong electronic interaction. The involvement of electronic interaction in H+/K+-ATPase inhibition has been shown by other authors also. We have, however, also found that biaryl imidazole derivatives can also undergo hydrogen bonding and hydrophobic interaction. A set of compounds that may have better activity have been predicted based on our QSAR model. By docking these compounds are shown to possess the activity even better than the marketed compounds.