Probing the Role of Imidazopyridine and Imidazophosphorine

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Article Cite This: ACS Omega 2019, 4, 1311−1321

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Probing the Role of Imidazopyridine and Imidazophosphorine Scaffolds To Design Novel Proton Pump Inhibitor for H+,K+‑ATPase: A DFT Study Kalyanashis Jana,†,‡ Shibaji Ghosh,†,‡ Padmaja D. Wakchaure,†,‡ Tusar Bandyopadhyay,§ and Bishwajit Ganguly*,†,‡ †

Computation and Simulation Unit (Analytical Discipline and Centralized Instrument Facility) and ‡Academy of Scientific and Innovative Research, CSIR-Central Salt and Marine Chemicals Research Institute, Bhavnagar 364002, Gujarat, India § Theoretical Chemistry Section, Chemistry Group MOD LAB, Bhabha Atomic Research Centre, Trombay, Mumbai 400085, India ACS Omega 2019.4:1311-1321. Downloaded from pubs.acs.org by 95.181.176.86 on 01/21/19. For personal use only.

S Supporting Information *

ABSTRACT: Clinically used proton pump inhibitors (PPIs) are not perfectly suitable for prolonged acid suppression because of the short plasma half-lives of 1−1.5 h. However, tenatoprazole, an imidazopyridine-type PPI, having a prolonged plasma half-life, is a promising replacement of the currently used PPIs. We have designed inhibitors that can possess imidazopyridine and imidazophosphorine units and can ease the formation of disulfide complex, which is one of the crucial steps toward the efficacy of PPIs. The M11LSMDWater/6-31++G(d,p)//M062X/6-31++G(d,p) level of theorycalculated results demonstrated that the acid activation of the imidazopyridine PPIs is complex than that of benzimidazole-type PPIs because of the presence of additional nitrogen, which could be protonated. However, the proton transfer from protonated pyridine nitrogen (PyNH+) to benzimidazole nitrogen(3) (BzN(3)) is more energetically favorable than that of protonated benzimidazole nitrogen(4) (BzN(4)H+) to BzN3 and the BzN(3)H+ further converts to the acid-activated sulfenic acid. It is to mention here that the PyNH+ PPIs are more stable compared to BzN(4)H+ PPIs. Subsequently, the acid-activated sulfenic acid forms the disulfide complex with the cysteine amino acid residue to inhibit the gastric proton pump H+,K+-ATPase. The disulfide complex formation (TS4) is the rate-determining step of the gastric proton pump inhibition process. The density functional theory (DFT) calculations also reveal that the acid activation and disulfide complex formation of all of the PPIs are very similar to those of potent PPI omeprazole. The free-energy activation barrier for tenatoprazole is 47.0 kcal/mol with respect to the preceding intermediate sulfenic acid, and the disulfide complex is stable by 28.0 kcal/mol. The M11L-SMDWater/ 6-31++G(d,p) level of theory results reveal that the disulfide complex formation of the imidazophosphorine type of PPIs is marginally more favorable than that of the analogous imidazopyridine type of PPIs. The newly designed inhibitor-3 and inhibitor-5 possess the lowest activation free-energy barriers, i.e., 35.8 and 35.9 kcal/mol, respectively, in the rate-determining steps (TS4) and also achieve significant thermodynamic stability of the disulfide complex. Steered molecular dynamics simulations performed with representative tenatoprazole and inhibitor-5 corroborated the DFT results.

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Hence, the patients may need to double the PPI dose, the first dose before breakfast and the second dose before dinner.11 Timoprazole, the basic scaffold of many irreversible PPIs, consists of two heterocyclic moieties: pyridine and benzimidazole moieties.12,13 The heterocyclic aromatic moieties are connected through a methylenesulfinyl (−CH2SO−) group. Omeprazole, a derivative of timoprazole, is one of the first clinically used potent PPIs, and other clinically used PPIs are pantoprazole, ilaprazole, lansoprazole, and rabeprazole. All of the marketed proton pump inhibitors have one, two, or more

INTRODUCTION

Proton pump inhibitors (PPIs) are a class of covalent inhibitors of the gastric pump H+,K+-ATPase introduced in the clinical treatment of peptic ulcer disease, erosive oesophagitis, and other acid-related disorders in 1989.1 PPIs are known to be significantly more effective and prolong acid suppressant compared to histamine-2 receptor antagonists.2−5 It has been reported in the literature that a significant number of patients suffering from acid-related disorders do not effectively respond to once or even twice daily PPI therapy.6,7 In the case of patients with oesophagitis, inflammation of the lining of the esophagus, PPIs display lower healing rates than the general gastroesophageal reflux disease population.8−10 © 2019 American Chemical Society

Received: October 11, 2018 Accepted: January 2, 2019 Published: January 15, 2019 1311

DOI: 10.1021/acsomega.8b02756 ACS Omega 2019, 4, 1311−1321

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remote substituents at pyridine and benzimidazole moieties. It is to note here that all of the PPIs consist of two optical isomers (enantiomers), one being the mirror image of the other, and exist as a racemic mixture.14−16 The S-isomer of all of the reported PPIs subsequently proved clinically superior compared to the racemic mixture or the R-isomer of that particular PPI.14,17 It is reported that the acid activation mechanism and disulfide complex formation of the S- and Risomers are energetically similar. However, their efficacy depends on the excretion from the human body.18−20 On the other hand, reports revealed that the pharmacological and pharmacokinetic properties of the currently marketed PPIs are not ideal for prolonged acid suppression because of the short plasma half-lives of the marketed PPIs, which range from 1 to 1.5 h.21 Therefore, PPIs can inhibit the proton pump only during this period, when the drug is available in the plasma. The gastric pumps, which are covalently bonded by available PPI, will remain blocked and cannot secrete acid actively. However, newly synthesized gastric proton pump will not be inhibited after plasma levels of the PPI dropped, and the newly synthesized pump, therefore, will not be able to secrete at full strength.22 Consequently, it is noteworthy to design a PPI having prolonged half-life to produce longer-time blockade of gastric proton pumps with the potential for more significant acid suppression activity for patients with postprandial evening and night-time symptoms. It is worth mentioning here that many research groups have been designing PPIs and potassium-competitive acid blockers to explore more effective as well as long-term acid inhibition.23−26 Abe et al. have been extensively studying proton pump inhibitor as well as designing novel potassium-competitive acid blockers.27−30 For the first time, Abe et al. reported crystal structures of gastric proton pump H+,K+-ATPase, which significantly helps in studying gastric proton pump. Tenatoprazole is the anticipated new PPI, which has a prolonged plasma half-life compared to other current PPIs.6,21,31−33 Therefore, tenatoprazole is reported to be an effective acid inhibitor throughout the 24 h period and, in comparison to the currently marketed PPIs, produced significant inhibitory activity in the later part of the day as well as through the night. The potent PPI tenatoprazole, which is the structural analogue of omeprazole, comprises the imidazopyridine moiety instead of the benzimidazole moiety of omeprazole. The mechanistic pathways for the acid activation and disulfide complex formation of tenatoprazole are scarce in the literature. It would be noteworthy to examine how the presence of additional nitrogen (BzN(4)) influences the acid activation mechanism of tenatoprazole compared to that of omeprazole. In this study, we have therefore undertaken a study to compare acid activation and disulfide complex formation mechanisms of tenatoprazole at the molecular level. The prolonged acid suppression activity of tenatoprazole inspires us to design a new class of PPI (imidazophosphorine series), which could have longer plasma half-life to inhibit the acid secretion for the 24 h period (Schemes 1 and 2) and which could be more effective in their acid activation process in the parietal cell. To explore the role of remote substituents and the chemical scaffold of the proton pump inhibitors, we have explored using computational study imidazopyridine and imidazophosphorine analogues of omeprazole, ilaprazole, lansoprazole, and rabeprazole (Scheme 2) in aqueous phase at the M11L-SMDWater/6-31++G(d,p)//M062X/6-31++G(d,p) level of theory.

Scheme 1. Imidazopyridine- and Imidazophosphorine-Type Inhibitors Examined in This Study

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RESULTS AND DISCUSSION PPIs, a class of weak bases, are composed of a substituted benzimidazole or imidazopyridine moiety linked via a methylenesulfinyl bridge to a substituted pyridine ring. Hence, PPIs consist of two or three nitrogen atoms, which are protonated in the acidic environment of the parietal cell. The protonation of these nitrogens is one of the important steps in the multistep acid activation of the prodrug PPIs. Therefore, it is noteworthy to examine the most negativevalued point (Vmin) in electron-rich regions of the PPIs. We have calculated Vmin from the molecular electrostatic potential (MESP) topography calculations and is given in Table 1. The Vmin calculations for tenatoprazole predict that benzimidazole N(4), BzN(4) (67.1 kcal/mol), has a greater Vmin value compared to the pyridine nitrogen, PyN (58.7 kcal/mol), and benzimidazole N(3), BzN(3) (60.5 kcal/mol), for tenatoprazole. Therefore, one would expect that the BzN(4) of tenatoprazole should be protonated before the pyridine nitrogen and Bz(N3) (Figure 1). In this context, we have examined the protonation mechanism of all of the three nitrogens of tenatoprazole (Figure 2). Interestingly, the protonation free energies for PyNH+, BzN(3)H+, and BzN(4)H+ are −4.2, 1.9, and −2.7 kcal/mol, respectively. The protonation free-energy activation barrier for BzN(4)H+ → BzN(3)H+ is 61.1 kcal/mol, whereas PyNH+ → BzN(3)H+ is barrierless. We could not locate the transition state (TS) for BzN(4)H+ → PyNH+ on the potential free-energy surface. It seems that the intramolecular proton transfer is not possible from BzN(4) to BzN(3) and PyN. Therefore, the only possible proton-transfer option is PyN to BzN(3) in the acid activation process of tenatoprazole. Furthermore, we have examined the water-assisted protontransfer processes for tenatoprazole. The hydronium (H3O+) ion-mediated protonation free energies for PyNH+, BzN(3)H+, and BzN(4)H+ are −10.7, −5.3, and −7.2 kcal/mol, respectively. The activation free-energy barriers for waterassisted PyNH+ → BzN(3)H+(TS1a-W), PyNH+ → BzN(3)H+(TS1b-W), and BzN(4)H+ → PyNH+(TS1c-W) are −1.8, 5.1, and 3.5 kcal/mol. The density functional theory (DFT) calculations reveal that the initial acid activation steps of imidazopyridine-type drug tenatoprazole are more complex than those of typical benzimidazole-type PPIs. However, the proton transfer from PyNH+ to BzN(3) is a barrierless process, and to BzN(3)H+ leads to the formation of further acidactivated intermediate. Furthermore, we have examined pKa values of all of these nitrogen atoms (Table 2). 1312


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Scheme 2. Two Major Classes of the Examined Inhibitor Molecules: Imidazopyridine and Imidazophosphorine Types

Table 1. Vmin Values Calculated at the M11L/6-31++G(d,p) Level of Theory (in kcal/mol) tenatoprazole inhibitor-1 inhibitor-2 inhibitor-3 inhibitor-4 inhibitor-5 inhibitor-6 inhibitor-7

PyN

BzN(3)

BzN(4)

58.7 59.2 54.7 54.2 51.2 52.0 58.6 59.1

60.5 57.5 55.1 51.8 54.8 52.2 58.7 56.0

67.1

to sulfenic acid, the acid-activated form of PPIs. The sulfenic acid reacts with the cysteine amino acid residues of the H+,K+ATPase to inhibit the acid secretion in the parietal cell through covalent disulfide bond formation. The disulfide complex formation between the cysteine amino acid residue and PPIs is the rate-determining step of the gastric proton pump inhibition process. In our earlier reports, we have observed that the formation of the tetracyclic sulfenamide intermediate is kinetically and thermodynamically unfavorable compared to the disulfide complex formation (Figures 3 and 4). To explore the role of the substituents in designing novel proton pump inhibitors, we have examined the acid activation and disulfide complex formation with the cysteine amino acid residue using reported and designed PPIs. The DFT calculations have been performed with imidazopyridine- and imidazophosphorine-type proton pump inhibitors. Tenatopra-

52.2 62.2 65.3

Pyridyl nitrogen attacks at C-2 of benzimidazole moiety to form the spiro intermediate in the acid activation pathway of tenatoprazole. The spiro intermediate undergoes aromatization

Figure 1. Molecular electrostatic potential of PPIs. Red isosurface represents the more electron-rich point on the MESP. 1313


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Figure 2. Plausible protonation and acid activation of imidazopyridine-type inhibitor molecules in the absence and presence of hydronium ion.

with inhibitor-2, inhibitor-4, and inhibitor-6. The activation free-energy barriers for inhibitor-2, inhibitor-4, and inhibitor-6 are 38.5, 36.9, and 37.9 kcal/mol, respectively, compared to the preceding intermediate sulfenic acid. The disulfide complex is stable by 26.8 kcal/mol for inhibitor-2, 23.7 kcal/mol for inhibitor-4, and 23.4 kcal/mol for inhibitor-6. The activation free energy for the disulfide formation significantly lowered compared to tenatoprazole, whereas the stability of the disulfide complexes is generally comparable. Therefore, the designed PPIs exhibit all of the properties to be an efficient inhibitor of the gastric acid for a longer time. Furthermore, we have designed a completely new class of PPIs having imidazophosphorine moiety instead of the benzimidazole and imidazopyridine moieties. We have endeavored to design phosphorylated PPIs because phosphorus is an essential nutrient required for critical biological processes in maintaining the normal homeostatic control of the cell.34−38 Phosphorus is one of the essential elements of different cellular structures, including nucleic acids and cell membranes. Optimum phosphorus−calcium balance is vital for maintaining skeletal growth, development, maintenance, as well as basic cellular functions, ranging from energy metabolism to cell signaling.37,38 Inhibitor-1, inhibitor-3, inhibitor-5, and inhibitor-7 are the imidazophosphorine analogues of omeprazole, ilaprazole, lansoprazole, and rabeprazole, respectively (Scheme 2). The pKa value calculations show that all of the newly designed imidazophosphorine inhibitors are weak bases, whose pKa values lie between 1 and 3 (Table 2). The M11LSMDWater/6-31++G(d,p) level of theory aqueous-phase calculations reveal that the TS4 activation free-energy barriers significantly decrease compared to tenatoprazole as observed with inhibitors 2, 4, and 6. On the other hand, the stability of the disulfide complexes is comparable to that of corresponding imidazopyridine inhibitor molecule (Table 3). The TS4 activation free-energy barrier for inhibitor-3, an imidazophosphorine inhibitor, is 35.8 kcal/mol, which is the

Table 2. pKa Values of the Examined PPIs as Well as the Designed Inhibitor Molecules at the M062X/6-31++G(d,p) Level of Theory tenatoprazole inhibitor-1 inhibitor-2 inhibitor-3 inhibitor-4 inhibitor-5 inhibitor-6 inhibitor-7

PyN

BzN(3)

2.6 2.5 2.0 1.5 −0.3 −1.5 4.0 4.5

−2.4 −1.2 −2.1 −2.5 −2.5 −1.3 −1.8 −1.9

BzN(4) 1.0

experimental pKa 4.04

−1.7 1.5 2.3

zole is the only reported imidazopyridine PPI, which shows long plasma half-lives and hence inhibits acid secretion for a longer time. The disulfide complex formation is the ratedetermining and one of the significant steps in the acid inhibition pathway. Therefore, we have focused on the activation free energy and the stability of the disulfide complex. The M11L-SMDWater/6-31++G(d,p)//M062X/6-31++G(d,p) level of theory-calculated results show that the TS4 activation free-energy barrier for tenatoprazole (TS4-tenatoprazole) is 47.0 kcal/mol compared to the sulfenic intermediate and the disulfide complex is stable by 28.0 kcal/mol compared to the neutral tenatoprazole. To increase the efficacy of tenatoprazole to inhibit acid secretion for a longer period, we have extended our computational efforts to design imidazopyridine-type inhibitors with the motivation that the disulfide complex formation is relatively easier than that of the former drug. Inhibitor-2, inhibitor-4, and inhibitor-6 are imidazopyridine derivative of ilaprazole, lansoprazole, and rabeprazole, respectively (Scheme 2). A PPI having comparably higher activation free-energy barrier for the TS4 and lower stability of the disulfide complex seems not to be a potent PPI, such as timoprazole. We have examined the acid activation and disulfide complex formation 1314


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Figure 3. Tenatoprazole acid activation mechanism in the absence and presence of hydronium molecule at the M062X/6-31++G(d,p) level of theory.

lowest among the examined PPIs, whereas inhibitor-1 forms the most stable disulfide complex with the cysteine amino acid residue. The DFT-calculated results revealed that the activation free-energy barrier for disulfide bond formation for PPIs depends on the stability of the preceding intermediate sulfenic acid along with the stability of the transition state itself. The M062X/6-31++G(d,p) level of theory optimized geometry analysis revealed that the disulfide complex formation occurs through a four-membered ring formation

followed by dehydration (Figure 5). We have not observed any significant difference between transition states of the imidazopyridine- and imidazophosphorine-type analogues. The distances between two sulfur atoms, S···S, in the TSs are 2.59, 2.0 Å for S···O, 1.84 Å for S···H, and 1.06 Å for O···H. However, the stabilizing hydrogen bond distances for BzN(3)···H are 1.80, 1.76, and 1.77 Å in S-omeprazole-TS4, tenatoprazole-TS4, and inhibitor-1-TS4, respectively. Dihedral analyses show that orientations of the pyridine and benzimidazole ring in S-omeprazole (130°) and the pyridine 1315


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Figure 4. Acid activation and disulfide complex formation of imidazopyridine- and imidazophosphorine-type inhibitor molecules.

Table 3. Acid Activation and Disulfide Complex Formation Free Energies Calculated at the M11L-SMDWater/6-31++G(d,p) Level of Theory (in kcal/mol)a tenatoprazole inhibitor-1 inhibitor-2 inhibitor-3 inhibitor-4 inhibitor-5 inhibitor-6 inhibitor-7

PyNH+

BzN3-H+

BzN4-H+

TS1

TS2

spiro

TS3

sulfenic acid

−4.2 −3.9 −3.4 −3.5 −0.2 −0.6 −5.9 −6.5

1.9 0.6 1.5 2.6 2.4 1.1 1.3 1.7

−2.7

1.4 2.6

10.5 8.6 5.3 5.9 5.6 11.7 8.2 8.5

2.8 3.8 −4.2 −1.9 5.3 6.6 −0.4 1.1

10.3 10.5 4.2 5.2 6.5 13.4 8.0 7.6

−5.0 −5.4 −3.8 −3.1 −1.8 −1.8 −0.2 −0.8

1.1 −3.3 4.0 −4.4

TS4 42.0 37.9 34.7 32.7 35.1 34.1 37.7 36.2

(47.0) (43.3) (38.5) (35.8) (36.9) (35.9) (37.9) (37.0)

disulfide −28.0 −29.1 −26.8 −26.9 −23.7 −23.7 −23.4 −23.4

a

Values in parenthesis are with respect to the preceding intermediates.

Figure 5. Disulfide complex formation through a four-membered ring formation followed by dehydration. The key distances are given in angstrom.

residue on the transition states of ligand−enzyme complex.41−43 We have also extended our study using the QM/ MM ONIOM approach with the residues of the binding site of H+,K+-ATPase on the rate-determining activation barrier in the inhibition process. TS4 is the rate-determining step in the overall inhibition mechanism of H+,K+-ATPase The activation barriers calculated with the binding-site residues of H+,K+ATPase and TS4 suggest that the residues lower the energy barrier significantly in both tenatoprazole and inhibitor-5 by ca. 70−80 kcal/mol (Figures S1 and S2). The free-energy activation barriers have not been compared in ONIOM calculations as approximations are involved using the universal force field (UFF).

and imidazophosphorine ring in inhibitor-1 (128°) are almost same. On the other hand, the dihedral angle between the pyridine and imidazopyridine ring in tenatoprazole is 122°. We have observed similar geometrical orientations and distances in the transition-state structures. Therefore, the acid activation and the disulfide complex formation of the examined PPIs are structurally similar. There are several reports on quantum chemical calculations in studying conformational preferences, kinetics of protein folding, mechanistic pathways of enzyme kinetics, and structure-based and ligand-based drug design processes.18,19,23,24,39,40 The quantum mechanics (QM) study using the ONIOM QM/molecular mechanics (MM) method has also been performed to study the influence of binding-site 1316


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Figure 6. NCI plots for tenatoprazole, inhibitor-3, and inhibitor-5. Noncovalent interactions in TS4s are shown using the color-filled RDG isosurface as well as scatter graph. The blue, green, and red circles represent hydrogen (H) bond, van der Waals (vdW), and steric repulsive interactions, respectively.

of tenatoprazole is found to be 344.2 kJ/(mol nm), while that for inhibitor-5 is 360.6 kJ/(mol nm). The center of mass (COM) separation analysis suggests that inhibitor-5 interacts with the cysteine-813 amino acid residue for a longer time than the tenatoprazole drug molecule. The ligand unbinding transition obtained by SMD simulation reveals that inhibitor-5 enjoys better noncovalent interaction up to the initial 500 ps. However, the tenatoprazole unbinding transition shows comparably weaker interaction (Figures 7 and 8).

The noncovalent interaction (NCI) analyses using noncovalent interaction (NCI) plots reveal that no significant difference in the noncovalent interaction occurs in the corresponding transition states. The NCI index is derived from the electron density ρ(r) and the reduced density gradient (s) as RDG(r ) =

|∇ρ(r )| 1 + 2 1/3 2(3π ) ρ(r )3/4

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It is to mention here that the NCI index has been recommended as an important approach to differentiate and visualize different types of noncovalent interactions. It appears that the difference in the stability of TS4 for inhibitor-1 compared to tenatoprazole-TS4 is due to the occurrence of strong steric effect in the later transition state (Figure 6). The stabilization of TS4 for inhibitor-3 and inhibitor-5 compared to tenatoprazole has been examined with NCI calculations. The NCI plots reveal that the steric interaction is larger in the case of tenatoprazole compared to these designed inhibitors, which in turn presumably raise the activation barrier in the former system (Figure 6).

CONCLUSIONS In this work, we have explored the role of the chemical scaffold in designing PPIs for prolonged acid suppression using DFT calculations. The clinically used as well as marketed PPIs are not ideal for prolonged acid suppression because of their short plasma half-lives. We aim to design inhibitors that could inhibit

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MD SIMULATION We have further carried out steered molecular dynamics (SMD) simulations to examine the role of the active site amino acid residue in stabilizing the drug molecules. It is reported that the SMD simulation technique is suitable for the study of time-dependent unbinding of the ligand molecule from the active site of the protein.44−48 The time-dependent unbinding of the inhibitor molecule from the active site of the protein in SMD simulation has been performed with the application of an external harmonic pulling force on the inhibitor molecule in the z direction, which is considered as a favorable exit route from the active site.44,45 We have considered 2YN9 Protein Data Bank (PDB) ID for the molecular dynamics simulation with tenatoprazole and inhibitor-5 as a representative case.49 The maximum ligand unbinding force required for unbinding

Figure 7. Ligand unbinding transition force profile for efficient proton pump inhibitor tenatoprazole and inhibitor-5. 1317


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potential energy surface at the same level of theory. All optimizations have been performed in the gas phase. The harmonic frequency calculations have been carried out at the same level of theory to confirm minima of optimized geometries having no imaginary frequencies, whereas transition state is confirmed with one imaginary frequency. M062X is reported as one of the accurate DFT functionals to explore their reactivity and stability of organic and ionic systems.53,54 We have further performed intrinsic reaction coordinate calculation to connect the TS geometries with the initial and final complexes.55 The M062X/6-31++G(d,p) level of theory optimized geometries were taken for single point energy calculations at M11L/6-31++G(d,p) in the aqueous phase (ε = 78.8) with the self-consistent reaction field method using the SMD solvation model.56,57 The SMD solvation model is considered as a universal solvation model, where “universal” denotes its suitability to any charged or uncharged solute in any solvent or liquid medium for which a few key descriptors are known. We have calculated the aqueous-phase free energy using the following equation

Figure 8. Center of mass (COM) separation between the ligand molecule and cysteine 813 amino acid residues.

the gastric acid secretion for a longer time. Earlier reports revealed that the disulfide complex formation with the cysteine amino acid residue is crucial for the efficacy of PPIs. We have performed DFT calculations at the M11L-SMDWater/6-31+ +G(d,p)//M062X/6-31++G(d,p) level of theory to explore the acid activation of the tenatoprazole. Tenatoprazole is a promising replacement of current PPIs since it can inhibit the gastric acid secretion throughout the day because of the prolonged plasma half-life. However, the DFT-calculated results showed that the acid activation of the imidazopyridine PPIs is more complex because of the presence of additional nitrogen, which could be protonated. The proton transfer from PyNH+ to BzN(3) is energetically favorable, and BzN(3)H+ is further converted to acid-activated sulfenic acid. Subsequently, the acid-activated sulfenic acid forms the disulfide complex with the cysteine amino acid residue. The disulfide complex formation step (TS4) is the rate-determining step of the gastric proton pump inhibition process. We have further designed inhibitors for the gastric proton pump H+,K+-ATPase replacing the benzimidazole moiety of the currently marketed PPIs, i.e., omeprazole, ilaprazole, lansoprazole, and rabeprazole, with imidazopyridine and imidazophosphorine scaffolds. The calculated results show that the acid activation and the disulfide complex formation of all of the newly designed PPIs are very similar. The M11L-SMDWater/6-31++G(d,p) level of theory results showed that the disulfide complex formation of the imidazophosphorine type of PPIs is more favorable than that of the analogous imidazopyridine inhibitors. The newly designed inhibitor-3 and inhibitor-5 possess the lowest activation free-energy barrier for TS4 with the significant stability of the disulfide complex. The force profiles calculated employing steered molecular dynamics simulations for the interaction of inhibitor-5 and tenatoprazole showed that the designed inhibitor binds strongly with H+,K+-ATPase. This study would be useful to researchers to perform the pharmacological and pharmacokinetics study required to examine the plasma half-life for their practical applications.

Gaq = Eaq + Gcorrection,gas

(1)

where Gaq is the aqueous-phase free energy, Eaq is the aqueousphase energy, and Gcorrection,gas is the free-energy correction value of the gas phase. The free-energy differences were calculated as ΔG = G X − G N

(2)

where GX is the free energy of the intermediate or transition state, GN is the free energy of initial molecules, and ΔG is the difference in the free energies. pKa calculations BzPyH+BzPy + H+ pK a =

ΔGaq (3)

2.303RT

ΔGaq = Gaq,BzPy + Gaq,H+ − Gaq,BzPyH+

(4)

Gaq has been calculated using eq 2 and Gaq,H+ = 266.24 kcal/ mol, as shown in main text (eq 4). The molecular electrostatic potential (MESP) is calculated using eq 5 N

V (r ) =

∑ A

ZA − |r − RA|

∫

ρ(r′) d3r′ |r − r′|

(5)

where ZA is the charge on nucleus A, located at RA, and ρ(r′) is the electron density.58 The electron-rich regions are generally revealed by a highly negative MESP; on the other hand, the electron-deficient regions are considered by positive MESP.59−62 The most negative-valued point (Vmin) in electron-rich regions is calculated from the MESP topography calculation, as discussed in earlier reports.49,63,64 The MESP calculations have been performed at the M11L/6-31++G(d,p) level of theory. All of the above density functional calculations have been carried out using Gaussian 09 software package (G09).65 ONIOM QM/MM Study. ONIOM double-layer calculations were performed in Gaussian 09 to examine the role of binding-site residues on transition-state barriers. Tenatoprazole and inhibitor-5 with binding-site residues are optimized. The transition state was treated with m062x/6-31g(d), and the

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COMPUTATIONAL METHODS Quantum Chemical Study. Acid-activated geometries of imidazopyridine- and imidazophosphorine-type inhibitors have been optimized at the M062X/6-31++G(d,p)50−52 level of theory. We have located transition states (TSs) on the 1318


ACS Omega second layer of residues was treated with MM force-field UFF. The ONIOM optimized geometries were taken for single-point calculations at M11L/6-31++G(d,p) in aqueous phase using the SMD solvation model to obtain the energies. Molecular Docking. The crystal structure for H+,K+ATPase enzyme (2YN9) was obtained from Protein Data Bank (PDB).66 Macromodel program was for addition of the hydrogens and energy minimization of the protein structure.67 All of the designed molecules were docked in the active site of the α-subunit of H+,K+-ATPase enzyme. All of the docking calculations were done using AutoDock 4.2 program.68 Molecular Dynamics Simulation. For molecular dynamics simulation, GROMACS-4.5.5 was used with Amber-03 force field.69 Force fields for all ligands were generated using Automated Topology Builder version 2.2, which is an online available server.70,71 The protein−drug complex was kept in a rectangular box of dimensions 10 × 12 × 25 nm3, where the complex is kept 16 Å away from the box wall. System was solvated using the 94189 TIP4P water model. To neutralize the system, 18 sodium ions were added to the solvated complex. The neutralized system with water molecules is energy-minimized, followed by heating with NVT simulation for 500 ps at 300 K using V-rescale temperature coupling with 1 ps coupling time. After NVT heating, NPT simulation for 500 ps is carried out at 300 K using V-rescale temperature coupling with 1 ps coupling time and Berendsen pressure coupling with 2 ps coupling time.72 Electrostatic interactions are considered using the particle-mesh Ewald algorithm with a distance cutoff of 15 Å.73 For the van der Waals (vdW) interactions, smoothing function was employed at a distance of 15 Å and nonbonded interactions list was updated every 20 time steps for pairs within a distance cutoff of 15 Å. After performing all of those equilibration steps, a steered molecular dynamics simulation was carried out for 5 ns, to mimic the transport process of a guest molecule through a nanochannel.74 We have applied a harmonic force constant of 1586.747 kJ/ (mol nm2) to the center of mass (COM) of the ligands with a pulled velocity of 0.0005 nm/ps.

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ACKNOWLEDGMENTS

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REFERENCES

CSIR-CSMCRI registration number - 215/2019. K.J. thanks UGC, New Delhi, India, for awarding a senior research fellowship. P.D.W. acknowledges CSIR, New Delhi, India, for the GATE-junior research fellowship. K.J. and P.D.W. are thankful to AcSIR for his Ph.D. registration. The present computational work is supported by Department of Atomic Energy, Government of India, Board of Research in Nuclear Sciences (DAE-BRNS) under grant no. 2013/37C/54/BRNS/ 2278. B.G. thanks DST, and DBT, New Delhi for financial support.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.8b02756. ONIOM calculations and geometries of the calculated structures; TS4 of tenatoprazole (Figure S1) and inhibitor-5 (Figure S2) with binding-site residues of H+,K+-ATPase (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected], gang_12@rediffmail.com. Tel: +91-278-2567760, ext 6770. Fax: (+91)-278-2567562. ORCID

Kalyanashis Jana: 0000-0001-9792-8195 Tusar Bandyopadhyay: 0000-0002-9359-6303 Bishwajit Ganguly: 0000-0002-9858-3165 Notes

The authors declare no competing financial interest. 1319


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