Journal of Applied Biopharmaceutics and Pharmacokinetics, … · 2018. 5. 7. · Izhar Ahmad1,...

20 Journal of Applied Biopharmaceutics and Pharmacokinetics, 2016, 4, 20-39

E-ISSN: 2309-4435/16 © 2016 Synchro Publisher

Quantitative Structure-Activity Relationship and Molecular Modeling Studies on a Series of H+-K+-ATPase Inhibitors

Izhar Ahmad1, Basheerulla Shaik1, Neelu Singh2, Vijay K. Agrawal3, K. Anitha4 and Satya P. Gupta1,*

1National Institute of Technical Teachers’ Training and Research, Bhopal-462002, India; 2Sagar Institute of Research and Technology-Excellence, Ayodhya Bypass, Bhopal, India; 3Department of Chemistry, APS University, Rewa, India and 4Department of Chemistry, Career College, Bhopal, India

Abstract: Quantitative structure-activity relationship (QSAR) and molecular modeling studies have been performed on a large series of H+-K+-ATPase inhibitors. A multiple linear regression (MLR) analysis exhibited that these inhibitors involve electronic interactions with the receptor. Using this MLR model, a few highly potent compounds were predicted whose docking in the enzyme exhibited that all of them form strong hydrogen bonds with the receptor and undergo dispersion interactions with some sites of the enzyme. The docking results of these compounds were found to have as good interactions with the enzyme as the FDA approved compounds, omeprazole, lansoprazole, rabeprazole, and pantoprazole.

Keywords: H+-K+-ATPase inhibitors, Proton pump inhibitors, QSAR study, Docking study.

1. INTRODUCTION

One of the diseases that have significant effect on the quality of human life and are the major burden on health care systems is gastroesophageal reflux disease (GERD) that leads to heart burn, acid regurgitation, chest pain, epigastric pain, and respiratory conditions such as chronic cough. This GERD is the result of hyperactivity of the enzyme H+,K+-ATPase, which is a member of the class 2C P-type ion-transport ATPases. H+,K+-ATPase is present in apical membranes of the parietal cells and is required for acid secretion. Parietal cells are epithelial cells that secrete hydrochloric acid (HCl). Since these cells are located in gastric glands, the acid secreted is known as gastric acid. The gastric acid is necessary for sterilization and the digestion of the food and is specially required for the activity of pepsin through the activation of pepsinogen [1]. H+/K+ -ATPase is unique to the parietal cells and transports the H+ against a concentration gradient of about 3 million to 1 (active transport).

GERD is a condition in which acid leaks into eso- phagus from the stomach. To treat hyperacidity and GERD, therefore, the inhibition of H+/K+-ATPase is highly desired. H+/K+-ATPase inhibitors are also known as proton pump inhibitors (PPIs). Currently, there are only a few PPIs approved to treat hyperacidity and GERD and they are omeprazole, lansoprazole, rabeprazole, and pantoprazole (Scheme 1). PPIs are acid- *Address correspondence to this author at the Department of Applied Sciences, National Institute of Technical Teachers’ Training and Research, Bhopal-462002, India; Tel: +91-8889534745; Fax: +91-755-2661996; E-mail: [email protected]

activated prodrugs that inhibit the hydrogen potassium ATPase by binding covalently to active pumps. Acid secretion is also blocked by H2-receptor antagonists (H2RAs) and acid pump antagonists (APAs), also called potassium-competitive acid blockers (PCABs), that block acid secretion by binding to the K+ active site. Though APAs provide faster inhibition than PPIs since they do not require acid activation, PPIs are the current treatment of choice [2], but they are often co-prescribed with other acid suppressive agents such as H2RAs [2]. Since the development of omeprazole in 1980s, the classical irreversible PPIs have drawn great attention [3].

The PPIs are prodrugs requiring activation to the corresponding cyclic sulfenamide [4], the rate of which is dependent on the basicity of the benzimidazole, the scaffold. Generation of the cyclic sulfenamide requires acidic conditions. Compared to histamine H2RAs, the irreversible mechanism of PPIs leads them to exert superior duration of elevated pH, resulting in superior healing of acid-related disorders [3], but they show an increased level of overall adverse effects than the H2RAs including diarrhea and headache, although these are still at a low level of incidence. Further, PPIs require acid activation and their plasma half-life is relatively short, therefore a significant proportion of the H+,K+-ATPase enzyme population remains uninhibited, delaying the full efficacy to be achieved with a PPI [5]. Another shortcoming of PPIs is the heterogeneity of response between patients due to variability in first-pass metabolism and therefore exposure [6-8]. PPIs undergo hepatic metabolism primarily by CYP2C19

QSAR and Molecular Modeling Studies Journal of Applied Biopharmaceutics and Pharmacokinetics, 2016, Vol. 4 21

and CYP3A4, the two enzymes of Cytochrome 450 family [9]. Both are liver enzymes that act on 10-15% of drugs in current clinical use. Such interactions have been reported with omeprazole [10]. Therefore, attempts have been made to generate longer acting PPIs that are more acid stable. PPIs have a good safety profile and there is no evidence of direct, clinically relevant toxic effects [11]. The safe clinical use of PPIs for near- ly 20 years is testament to this low risk from prolonged acid suppression in man [12-14]. A modification to the theme of PPIs has been discussed by Bamford [15] that include some reversible PPIs. The modifications in existing PPIs have been attempted to find more acid stable drugs. The results of substitution of the benzimidazole NH with acyloxyalkyl, alkoxycarbonyl, amino- ethyl and alkoxyalkyl groups have been discussed [16]. Now-a-days to design and develop any kind of drugs, QSAR and molecular modeling studies have been of great help. Therefore, in this communication, we present such a study on a large series of H+/K+ -ATPase inhibitors comprised of structurally different groups of chemicals compiled by Bamford [15].

2. MATERIAL AND METHODS

A large series of compounds as shown in Table 1 were compiled from Bamford [15]. In this table are also given the H+/K+-ATPase inhibition activity of the compounds, in terms of pIC50, and their structural parameters that were found to be correlated with the activity. The most important structural parameter that was found to govern the activity of the compounds was F03[N-N] that referred to frequency of N−N at topological distance 3 (2D Atom Pairs, Frequency Atom Pairs of order 3). Additionally, there were three indicator parameters,

I3cyc, ISO2Ar, and INH that refer to the presence of certain effective characteristics in the molecule. With the value of 1 each, they refer to the presence of a tricyclic ring, presence of an SO2-Ar group, and presence of an NH bridge between two cyclic moieties, respectively. A value of zero of these parameters indicates the absence of the corresponding groups. All the compounds present in Table 1 were divided into two sets, a training set containing 49 compounds and a test set containing 15 compounds. All the compounds in the test set were marked with a superscript ‘b’. Compounds for test set were selected considering the appreciable differences among their structures as well as among their activity values. Compounds with superscript ‘c’ in the table were those that behaved as outliers. They were not included in regression analysis. On these data, we performed a QSAR study using multiple linear regressio (MLR) analysis and the docking study using FlexX software.

3. RESULTS AND DISCUSSION 3.1. QSAR Study

When a multiple linear regression (MLR) analysis was performed on the compounds of the training set, a significant correlation as shown by eq. 1 was obtained, in which n refers to the number of data points used in the correlation, r is the correlation coefficient, r2

cv is the cross-validated correlation coefficient obtained by leave-one-out (LOO) jackknife procedure, and r2

pred is the square of correlation coefficient obtained for test set compounds to judge the external validity of the correlation. The value of r2

cv is calculated as shown by eq. 2, where yi,obsd and yi,pred are the observed and predicted (from LOO) activity values of compound i, respectively,

Omeprazole Lansoprazole

Rabeprazole Pentoprazole

Scheme 1: Licensed compounds available in the market to treat the hyperacidity and GERD.

22 Journal of Applied Biopharmaceutics and Pharmacokinetics, 2016, Vol. 4 Ahmad et al.

Table 1: A Series of Compounds Acting as H+,K+-ATPase Inhibitors, their Structural Properties and H+,K+-ATPase Inhibition Potency

No. Compound F03[N-N] I3cyc ISO2Ar INH pIC50 Obsda

Cald. eq. 1

Pred. LOO

1

O

NH

N

N

N

O

2 0 0 1 7.07 7.37 7.39

2

O

NH

N

N

N

O

2 0 0 1 7.21 7.37 7.38

3b

O

NH

N

N

N

O

2 0 0 1 7.55 7.37 -

4

O

NH

N

N

N

O

OH

2 0 0 1 7.30 7.37 7.38

5

O

NH

N

N

N

O

2 0 0 1 6.99 7.37 7.40

6

O

NH

N

N

N

O

OH

2 0 0 1 7.06 7.37 7.40


(Table 1) contd….


Cald. eq. 1

Pred. LOO

7

O

NH

N

N

N

O

OH

2 0 0 1 7.03 7.37 7.40

8 O

NH

N

N

N

O

F

2 0 0 1 7.85 7.37 7.34

9 O

NH

N

N

N

O

F

2 0 0 1 7.54 7.37 7.36

10b O

N

N

OH

0 0 0 0 6.60 6.64 -

11b O

N

N

OH

0 0 0 0 6.37 6.64 -

12 O

N

N

N

0 0 0 0 7.19 6.64 6.61


(Table 1) contd….


Cald. eq. 1

Pred. LOO

13 O

N

N

OH

0 0 0 0 7.19 6.64 6.61

14b

N

N

O

N

O

0 1 0 0 5.17 5.25 -

15

N

N

O

N

O

0 1 0 0 5.27 5.25 5.24

16

N

N

O

N

O OH

0 1 0 0 5.24 5.25 5.25

17

N

N

O

N

O OH

0 1 0 0 5.20 5.25 5.26

18

N

N

O

N

O

S

0 1 0 0 5.28 5.25 5.24

19b N

N

O

N

O

O

0 0 0 0 6.25 6.64 -


(Table 1) contd….


Cald. eq. 1

Pred. LOO

20

N

N

O

N

O

O

OH

0 0 0 0 6.37 6.64 6.66

21

N

N

O

N

O

O

0 0 0 0 6.49 6.64 6.65

22

O

F

O

N

NN

O

0 0 0 0 7.16 6.64 6.61

23

O

F

O

N

NN

O

0 0 0 0 6.68 6.64 6.64

24

O

F

O

N

NN

O

0 0 0 0 6.66 6.64 6.64


(Table 1) contd….


Cald. eq. 1

Pred. LOO

25b

O

F

O

N

NN

O

F

0 0 0 0 7.07 6.64 -

26 O

F

O

N

HN

N

O

F

0 0 0 0 7.01 6.64 6.62

27 O

F

O

N

HN

O

F

NH

0 0 0 0 7.52 6.64 6.59

28b

O

O

N

HN

N

O

0 0 0 0 7.17 6.64 -

29

O

O

N

HN

N

O

F

F

0 0 0 0 6.68 6.64 6.64

30

S

O

N

HN

N

O

0 0 0 0 6.80 6.64 6.63


(Table 1) contd….


Cald. eq. 1

Pred. LOO

31b O

NN

F

O

1 0 0 0 6.77 7.26 -

32 O

NN

F

1 0 0 0 6.74 7.26 7.28

33 O

NN

F

1 0 0 0 6.41 7.26 7.30

34b O

NN

F

O

1 0 0 0 5.74 7.26 -

35c O

NN

OClCl

1 0 0 0 5.63 - -

36 O

NN

F

N

O

2 0 0 0 7.55 7.87 7.91


(Table 1) contd….


Cald. eq. 1

Pred. LOO

37 NH

NN

F

2 0 0 1 7.03 7.37 7.40

38 N

NH

1 0 0 0 7.20 7.26 7.26

39 N

NN

2 0 0 0 8.40 7.87 7.82

40 N

NN

N

2 0 0 0 8.00 7.87 7.86

41b N

NN

H2N

O

3 0 0 0 8.82 8.49 -

42c N

NN

H2N

O

3 0 0 0 5.39 - -


(Table 1) contd….


Cald. eq. 1

Pred. LOO

43 N

NN

N

O

N

4 0 0 0 9.15 9.10 9.08

44 NH

NNH

2 0 0 1 7.57 7.37 7.36

45 NH

NN

F

2 0 0 1 7.62 7.37 7.36

46 NH

NN

F

HO

2 0 0 1 8.49 7.37 7.29

47

F

NH

NN

N

0 0 0 1 5.27 6.14 6.24

48

F

NH

NN

N

0 0 0 1 6.05 6.14 6.15


(Table 1) contd….


Cald. eq. 1

Pred. LOO

49b

F

NH

NN

N

0 0 0 1 6.30 6.14 -

50

F

NH

NN

N

0 0 0 1 6.15 6.14 6.14

51b N

N

N

F

HN

0 0 0 1 5.80 6.14 -

52 NH

NN

N

F

0 0 0 1 6.40 6.14 6.11

53c

F F

NH

NN

N

0 0 0 0 5.42 - -

54 NH

NN

NF

0 0 0 1 6.00 6.14 6.16

55b NH

NN

NF

F

0 0 0 1 6.52 6.14 -


(Table 1) contd….


Cald. eq. 1

Pred. LOO

56

NH

NN

N

F

F

0 0 0 1 6.70 6.14 6.08

57

O

N

OH

0 0 0 0 6.30 6.64 6.66

58 N

O

HO

0 0 0 0 6.22 6.64 6.67

59 N

O

HO

HO

0 0 0 0 5.74 6.64 6.70

60b N

O

HO

HO

0 0 0 0 6.05 6.64 -

61

S

N

HN

SO

O

0 0 1 0 5.38 4.92 4.69


(Table 1) contd….


Cald. eq. 1

Pred. LOO

62b N

HN

S OO

S

O

O

0 0 1 0 4.11 4.92 -

63 N

HN

S OO

S

0 0 1 0 4.48 4.92 5.14

64 N

HN

S OO

N

O

0 0 1 0 4.89 4.92 4.93

aTaken from Ref. [2]. bTest set compounds. cOutliers.

and yav,obsd is the average of the observed activities of all compounds used in the correlation. The correlation is supposed to be valid and have good internal predictive ability if r2

cv > 0.60. From this point of view, the correlation expressed by eq. 1 seems to be quite valid. However, the external predictive ability of any correlation equation is judged by predicting the activity of the compounds in the test set using it and calculating the value of r2

pred, which is defined as shown by eq. 3, where yi,obsd and yi,pred refer to the observed and predicted (from equation obtained) activity of compound i in the test set and yav,obsd is same as in eq. 2. The value of r2

pred > 0.50 indicates the good external predictive ability of the model. Among the remaining two statistical parameters, s and F, s is the standard deviation and F is the Fischer ratio between the variances of calculated and observed activities. The figures within the parentheses with ± sign are 95% confidence inter- vals. The F-value given in parenthesis refers to standard F-value at 95% level. A higher value of F than this

signifies a good correlation. All the statistical parameters suggest that eq. 1 represents a significant correlation where the parameter F03[N-N], suggesting the frequency of N−N at topological distance 3, is shown to have significant positive effect on the activity of the compounds. This parameter in fact means number of N-N pairs where both the nitrogens are separated by 3 bonds from each other. Such a separation between the two nitrogens may be crucial for the interaction of the molecule with the enzyme.

However, the negative coefficients of all the three indicator parameters I3cyc, ISO2Ar, and INH indicate that the presence of a tricyclic ring, or an SO2-Ar group, or an NH bridge in the molecule will be detrimental to the activity. The negative effect of tricyclic ring may be attributed to its bulk that might create the steric problem and that of SO2-Ar group and an NH bridge may be attributed to the lone pairs of electrons present on the two oxygen atoms in SO2 and on the nitrogen in NH. These electron pairs might produce the repulsive


effects in the electronic interactions with the active sites of the enzyme. All the variables used in this correlation are found to be quite significant, as if we remove them one by one, the significance of the correlation is appre- ciably dropped (eqs. 4-6).

pIC50 = 0.616(±0.145) F03[N-N] − 1.393(±0.500)I3cyc − 1.724(±0.564) ISO2Ar − 0.499(±0.308)INH + 6.641(±0.216)

n = 46, r = 0.903, r2cv = 0.777, r2

pred = 0.741, s = 0.447, F4,41 = 45.29(3.82) (1)

r2cv= 1 − [Σi (yi,obsd − yi,pred)2/ Σi(yi,obsd – yav,obsd)2] (2)

r2pred = 1 − [Σi (yi,obsd − yi,pred)2/ Σi(yi,obsd− yav,obsd)2] (3)

pIC50 = 0.537(±0.151) F03[N-N] − 1.238(±0.544)I3cyc − 1.569(±0.616)ISO2Ar + 6.641(±0.216)

n = 46, r = 0.876, r2cv = 0.729, r2

pred = 0.762, s = 0.496, F3,42= 46.14(4.29) (4)

pIC50 = 0.626(±0.185) F03[N-N] −1.047(±0.680)I3cyc + 6.294(±0.254)

n = 46, r = 0.788, r2cv = 0.585, r2

pred = 0.491, s = 0.625, F2,43 = 35.22(5.14) (5)

pIC50 = 0.695(±0.196) F03[N-N] + 6.148(±0.257)

n = 46, r = 0.732, r2cv = 0.498, r2

pred = 0.441, s = 0.684, F1,44 = 50.80(7.24) (6)

All the statistical parameters of eq.1 have suggest- ed that this equation represents a significant correlation between the activity and the structural variables of the compounds. Activity values predicted from this equation for both the training and test set compounds are found to be in good agreement with their corresponding observed ones (Table 1). This is also evident from the graph drawn between the predicted and observed activities (Figure 1). Using eq. 1, we have predicted some new compounds as shown in Table 2 that might prove to have very high potency as compared to any compound in the existing series (Table 1).

3.2. Docking Study

A docking study was performed on the predicted compounds using FlexX software to see the binding of these compounds with the H+-K+-ATPase. The ability of a molecule to interact with an enzyme decides its potency. For the study of docking, the crystal structure of the related enzyme, bound with substrate or any other ligand, is required which can now be retrieved from RCSB protein data bank (PDB). Then the ligand is

removed and attempt is made to dock the new ligand. In FlexX method, a core of the ligand that is to be docked is automatically selected to be placed into the active site of the enzyme. This core is placed into the active site using a new algorithmic approach based on a pattern recognition technique called pose clustering. Then the remainder of the ligand is built up increment- ally from other fragments. A new fragment is added in all possible conformations to all placements found in the previous iteration, but only the k best placements are taken on to the next construction step. The confor- mational flexibility of the ligand is included by generat- ing multiple conformations for each fragment and including all in the ligand building steps. Then place- ment of the ligand is scored on the basis of protein-ligand interactions and calculating the binding energy.

Figure 1: A graph of predicted activity vs observed ones.

We selected the enzyme with PDB entry code 2XZB (http://www.pdb.org). We can see that in Table 2, compounds 1, 6, 7, and 8 are shown to have equally high activity as compared to other compounds. However, all the compounds were docked in the protein molecule and compounds 1 and 8 were found to have highest docking scores. The docking results of all the predicted compounds are shown in Table 3. For the comparison, the docking results of four FDA approved compounds are also shown in the same table. Though we docked all the compounds in the enzyme, we are citing here the docked structures of only compounds 1 and 8 (Figures 2 and 3) just to exemplify how these inhibitors interact with the H+-K+-ATPase. For comparison, we are citing here the docked structures of only two FDA approved compounds, one that has the highest number of hydrogen bondings (Lansoprazole) (Figures 4) and the one that has the highest docking score (Pentapra- zole) (Figure 5). As one can see from these figures, the predicted compounds have as good interactions with the enzyme as the FDA approved compounds. They all


Table 2: Predicted Compounds

Compd. No Compound I3cyc ISO2Ar INH F03[N-N] pIC50

1

NN

O

N

N

N

OH

O

H2N

NH2

0 0 0 5 9.72

2

NN

O

N

N

N

OH

N

0 0 0 4 9.11

3

NN

O

N

N

N

OH

N

0 0 0 4 9.11

4

NN

O

N

N

N

OH

NH2N

0 0 0 4 9.11

5

NN

O

N

N

N

OH

O

0 0 0 4 9.11

6

NN

O

N

N

N

OH

H2N

O

0 0 0 5 9.72


(Table 2) contd….

Compd. No Compound I3cyc ISO2Ar INH F03[N-N] pIC50

7

NN

O

N

N

N

OH

H2N

O

0 0 0 5 9.72

8

NN

O

N

N

N

OH

NH

O

O

OH

0 0 0 5 9.72

9

NN

O

N

N

N

OH

O

O

O

0 0 0 4 9.11

10

NN

O

N

N

N

O

O

0 0 0 4 9.11

Figure 2: A representation of the binding of predicted compound 1 (Table 2) in H+-K+-ATPase (PDB entry code 2XZB).


Table 3: Docking Results

Compd. No. No. of H-Bonds H-Bonds H-Bonds Length (Å) Score

1 4

H(26)-Pro233 H(31)-Pr0233 N(32)-Arg560 H(76)-Gln234

4.70 4.70 4.62 2.70

-24.1573

2 2 H(31)-Thr632 O(14)-Arg560

2.27 4.62

-14.7719

3 3 O(14)-Ile631 H(27)-Gly556 N(39)-Arg560

3.32 1.57 3.89

-17.2798

4 3 H(27)-Glu232 H(28)-Gly556 N(32)-Arg560

4.70 4.09 2.28

-18.1161

5 4

N(6)-Arg560 N(15)-Arg560 N(15)-Arg560 H(31)-Asp602

0.49 0.40 4.61 4.70

-6.1420

6 4

O(14)-Arg560 H(32)-Glu232 H(39)-Glu232 O(39)-Asn675

4.62 4.70 8.30 4.32

-16.4238

7 4

H(32)-Pro233 N(32)-Arg560 H(39)-Pro233 H(86)-Gln234

4.70 4.61 4.70 2.42

-14.5653

8 5

H(30)-Gln392 H(36)-Gln392 O(43)-Gln392 O(44)-Arg605 O(44)-Arg605

4.50 4.70 3.72 5.81 6.07

-24.1330

9 4

O(14)-Ile631 O(35)-Arg560 O(39)-Arg560 O(39)-Arg560

4.34 3.54 5.51 5.31

-19.7426

10 2 O(14)-Arg560 H(86)-Glu232

4.62 8.30

-15.3464

Omeprazole 5

N(2)- Arg560 N(2)- Arg560 H(16)-Gly558 O(13)-Arg560 O(23)-Asp602

0.18 3.50 2.60 1.59 2.52

-12.4414

Lansoprazole 6

O(11)-Thr411 O(11)-Thr411 O(11)-Thr411 O(11)-Thr412 N(2)-Thr412 H(12)-Thr412

2.44 4.12 2.88 2.29 1.31 4.34

-11.5800

Rabeprazole 3 H(14)-Gly558 N(19)-Arg560 O(24)-Arg394

4.44 4.62 4.52

-14.3837

Pentaprazole 4

O(9)-Arg560 O(9)-Arg560 O(13)-Arg560 H(14)-Gly558

1.18 4.62 4.25 0.77

-15.9853


undergo the hydrogen bondings as well as steric interactions, in which several moieties of compounds are engulfed in the different active cavities of the enzyme. The penetration of any moiety of any inhibitor in any cavity of the enzyme will depend on its flexibility. All these steric interactions might involve the dispersion interactions. This is a kind of electronic interaction.

That the electronic properties of molecules play important roles in H+-K+-ATPase inhibition was also shown by many other QSAR studies performed by various authors on compounds not much different from those in Table 1 [17-23]. Recently, we also found for a series of biarylimidazole derivatives that H+/K+-ATPase inhibition predominantly involves only electronic interactions [24]

Figure 3: A representation of the binding of predicted compound 8 (Table 2) in H+-K+-ATPase (PDB entry code 2XZB).

Figure 4: A representation of the binding of one of the FDA approved compounds, lansoprazole, in H+-K+-ATPase (PDB entry code 2XZB). This compound has the highest number of H-bondings.


and so was the case when we performed a QSAR and molecular modeling study [25] on a fairly large series of heteroaryl- and heterocyclyl-substituted imidazopyridine derivatives, reported to have gastric H+/K+-ATPase in- hibitory potency and anti-secretory activity by Bailey et al. [26].

4. CONCLUSION

For a large series of structurally different compounds, it is found that the hydrogen bonding and dispersion interaction can be important interactions between the drug and H+-K+-ATPase enzyme. Further, it is observed that a tricyclic aromatic ring in the molecule may not be beneficial to the activity, probably due to its steric bulk. The active site of the enzyme may not be so flexible to accommodate a tricyclic ring. Further, the presence of moieties like SO2 and NH might not be beneficial, as the lone pair of electrons present on them might undergo repulsive electronic interactions with the active sites of the enzyme that may be constituted of the negatively charged residues.

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Figure 5: A representation of the binding of one of the FDA approved compounds, lansoprazole, in H+-K+-ATPase (PDB entry code 2XZB). This compound has the highest docking score.


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Received on 15-04-2016 Accepted on 06-05-2016 Published on 03-06-2016 DOI: http://dx.doi.org/10.20941/2309-4435.2016.04.3 © 2016 Ahmed et al.; Licensee Synchro Publisher. This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.

Journal of Applied Biopharmaceutics and Pharmacokinetics, … · 2018. 5. 7. · Izhar Ahmad1,...

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