Alimentary Pharmacology and Therapeutics
The binding selectivity of vonoprazan (TAK-438) to the gastric H+,K+-ATPase D. R. Scott*,†, K. B. Munson†,‡, E. A. Marcus†,§, N. W. G. Lambrecht¶ & G. Sachs*,†,‡
*Department of Physiology, DGSOM at UCLA, Los Angeles, CA, USA. † VA GLAHS, Los Angeles, CA, USA. ‡ Department of Medicine, DGSOM at UCLA, Los Angeles, CA, USA. § Department of Pediatrics, DGSOM at UCLA, Los Angeles, CA, USA. ¶ Pathology and Laboratory Medicine Service, VA Long Beach Healthcare System, Long Beach, CA, USA.
Correspondence to: Dr D. R. Scott, UCLA/VA GLAHS, 11301 Wilshire Blvd, Bldg. 113 Rm. 324, Los Angeles, CA 90073, USA. E-mail:
[email protected]
Publication data Submitted 28 July 2015 First decision 9 August 2015 Resubmitted 25 August 2015 Resubmitted 3 September 2015 Accepted 3 September 2015 EV Pub Online 30 September 2015 This article was accepted for publication after full peer-review.
SUMMARY Background The gastric H+,K+-ATPase is the preferred target for acid suppression. Until recently, the only drugs that effectively inhibited this ATPase were the proton pump inhibitors (PPIs). PPIs are acid-activated prodrugs that require acid protection. Once acid-activated, PPIs bind to cysteines of the ATPase, resulting in covalent, long-lasting inhibition. The short plasma half-life of PPIs and continual de novo synthesis of the H+,K+-ATPase result in difficulty controlling night-time acid secretion. A new alternative to PPIs is the pyrrolo-pyridine, vonoprazan (TAK-438), a potassium-competitive acid blocker (PCAB) that does not require acid protection. In contrast to other PCABs, vonoprazan has a long duration of action, resulting in 24-h control of acid secretion, a high pKa of 9.37 and high affinity (Ki = 3.0 gmol/L). Aim To determine binding selectivity of vonoprazan for the gastric H+,K+ATPase and to explain its slow dissociation. Methods Gastric gland and parietal cell binding of vonoprazan was determined radiometrically. Molecular modelling explained the slow dissociation of vonoprazan from the H+,K+-ATPase. Results Vonoprazan binds selectively to the parietal cell, independent of acid secretion. Vonoprazan binds in a luminal vestibule between the surfaces of membrane helices 4, 5 and 6. Exit of the drug to the lumen is hindered by asp137 and asn138 in the loop between TM1 and TM2, which presents an electrostatic barrier to movement of the sulfonyl group of vonoprazan. This may explain its slow dissociation from the H+,K+-ATPase and long-lasting inhibition. Conclusion The binding model provides a template for design of novel potassium-competitive acid blockers. Aliment Pharmacol Ther 2015; 42: 1315–1326
ª 2015 John Wiley & Sons Ltd doi:10.1111/apt.13414
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D. R. Scott et al. BACKGROUND Inhibition of the gastric H+,K+-ATPase, the gastric proton pump, is the preferred means of reducing acid secretion for the treatment of peptic ulcer disease and gastro-oesophageal reflux disease, and is required in combination with antibiotics for eradication of Helicobacter pylori. The currently available drugs that inhibit the H+, K+-ATPase are proton pump inhibitors (PPIs) such as omeprazole, esomeprazole, lansoprazole, dexlansoprazole, pantoprazole and rabeprazole. These are acid-activated prodrugs that convert to a thiophilic sulfenic acid and bind covalently to one or more cysteines of the alpha subunit of the ATPase, inhibiting acid secretion. Only active pumps are inhibited, and not all pumps are active at any one time. These drugs are administered before meals and steady state inhibition requires three to five days of once a day dosing. PPIs have a short plasma half-life of about 90 min and do not completely inhibit acid secretion because the half-life of the ATPase is about 50 h.1, 2 Hence, about one-third of the pumps are synthesised in 24 h, so that even with twice a day treatment, newly synthesised pumps will be secreting acid before the next administration of a PPI. This makes control of night-time acid secretion difficult.3 An alternative to PPIs, the potassium-competitive acid blockers (PCABs) or acid pump antagonists, were first discovered when a group of tertiary amines targeted to prevent Ca2+ accumulation were shown to inhibit acid secretion in rabbit gastric glands by K+-competitive inhibition of the gastric H+,K+-ATPase and not regulation of intracellular Ca2+.4 In the context of H+,K+ATPase inhibition, the terms inhibitor, blocker and antagonist are synonymous. Subsequently, an imidazopyridine, SCH28080 (Figure 1) was synthesised, targeted against acid secretion as a possible analogue of omeprazole, and shown to be an effective inhibitor of gastric acid secretion.5–9 Investigation of its mechanism showed that it was a purely K+-competitive inhibitor of the gastric H+,K+-ATPase with a Ki of ~60 nmol/L at pH 7.4.10 However, SCH28080 is hepatotoxic and was never developed for clinical use. Its pKa of 5.5 results in selective accumulation only in acid-secreting parietal cells, where the canalicular pH is 500 7.0 2.0 410
Type of inhibition
Vmax* (lmol/mg/h)
Km,app [NH4+] mmol/L + S.E.
Competitive None Competitive Competitive
88.0 6.0 99 109 11
2.3 1.5 0.9 2.1
0.1 0.2 0.2 0.2
* Vmax was normalised to protein expression. Standard errors for the Vmax and Ki calculated from assay data were proportional to those given for the Km,app. † Different standard preparations of porcine H+,K+-ATPase vary with respect to Vmax. ‡ Kinetic analyses over a range of ammonia concentrations resulted in no inhibition by vonoprazan for the A335C mutant. The Ki was estimated to be greater than 500 nmol/L for this mutant based on the absence of inhibition by 25 nmol/L vonoprazan in the presence of 1 mmol/L NH4+. § Asano et al. reported a 60–80% lower affinity for the alanine and serine mutants of Y799.25 Aliment Pharmacol Ther 2015; 42: 1315–1326 ª 2015 John Wiley & Sons Ltd
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D. R. Scott et al. (b)
(a)
TM2
TM6 leu141
ile816
TM1
TM3
cys120 met334
ala339
TM5
cys813
ala335
Methyl amino
TM1
leu811
TM4
asn138 pro798
Methylamino
TM2
pro810
(c) glu795
Sulfonyl TM5
TM4
leu809
TM6 Sulfonyl
TM5
TM6
asp137 tyr799
cys813
TM2 TM1
pro798 asp137
asn138
tyr799
Figure 6 | (a) Surfaces of the luminal vestibule (blue) and vonoprazan (stick, carbons in orange). The inhibitor is proposed to fit in the slot at the bottom of the vestibule as suggested for SCH28080 with the methylamino group (red arrow) next to TM5, the sulfonyl group (yellow arrow) facing TM2 near the start of TM6, and the fluorophenyl ring between TM5 and TM6 (helices coloured as in Figure 2). Only the outer edge of the fluorophenyl ring (centre) is exposed to the solvent. (b) Proposed binding site for vonoprazan (surface and stick with carbons in orange) with residues whose mutation affect binding (ball and stick) in cyan. The inhibitor fits in the loop between TM5 and TM6 (light orange and dark orange ribbons respectively) on one end and TM1 (blue ribbon) and TM4 (green ribbon) on the other (TM3 omitted). Mutation of tyr799 or ala335 (ball and stick) on one side of the bound inhibitor severely affects binding. Methoxy substitution in the sixth position of the pyridine ring (red circle) has been reported to give retention of high affinity H+,K+-ATPase inhibition while replacement of fluorine in the second position of the phenyl ring (blue circle) with methoxy gives a loss of more than 100-fold in affinity. (c) A nearly identical pose for vonoprazan (stick, carbons in blue) docking is found by an unbiased scoring algorithm (AutoDockVina). As found for the energy minimised conformation in (b), the inhibitor is oriented in the binding space with the methylamino group in next to an expanded turn in TM5 produced by pro798 and hydrogen bonding to the backbone carbonyl of glu795 (blue arrow). The sulfonyl oxygens face the sulfhydryl hydrogen from cys813. Asp137 and asn138 present a likely electrostatic barrier to the sulfonyl oxygens (red arrow) of the inhibitor for movement towards the open end of the vestibule and exit to the lumen (green arrow).
TM4, and the fluorophenyl pointing towards the vesicle opening near TM6. Connolly surface analysis of inaccessible surface area of vonoprazan showed the bound inhibitor has 89.2% of its total surface area (299.6 out of 336.0 A2) inaccessible in the bulk solvent. Therefore, vonoprazan is predicted to bury a larger surface area and a larger percentage of its surface than SCH28080. Clinically, this finding could at least partially explain why dissociation of vonoprazan from the H+,K+-ATPase is slower than SCH28080. Analysis of the detailed vonoprazan binding site interactions show the pyrrole and fluorophenyl rings stacked against the side chain of tyr799 while ala335 fits in the curvature between the pyrrole and pyridine rings in a manner analogous to the imidazopyridine ring of SCH28080 (Figure 6b). This docking mode accounts for 1322
the severe effects of mutating these two residues. The opposite surface of the fluorophenyl ring faces asp137, and asn138 (Figure 6b, black arrows), leu141 and cys813 with the sulphur of cys813 oriented towards the two sulfonyl oxygens within distances of 3.05 and 4.40 A respectively. The edges of the pyrrole and fluorophenyl rings are enclosed by ile816 and the TM5/TM6 loop from leu809 to cys813. The effect is to pin the pyrrole and fluorophenyl rings tightly in the space between tyr799 and ala335 on one side and asp137, asn138, leu141 and cys813 on the other. The lack of free movement and close proximity to cys813 suggests the specificity of vonoprazan for the gastric H+,K+-ATPase is partially due to the replacement of cysteine at this position with the beta-branched side chain of threonine in the Na+,K+-ATPase. The methyl moiety fits in the space Aliment Pharmacol Ther 2015; 42: 1315–1326 ª 2015 John Wiley & Sons Ltd
Binding of vonoprazan to the gastric H+,K+-ATPase between ala335 and ala339 with the amino group facing TM5 and hydrogen bonded to the backbone carbonyl of glu795 (Figure 6c, blue arrow). Space for the buried methylamino group between TM4 and TM5 (Figure 6b, red text) is given by an expanded turn in TM5 before pro798 (Figure 6c), which also makes the backbone carbonyl of glu795 available for hydrogen bonding. One of the K+ binding sites is in the vicinity of glu795.27 The orientation of the pyridine ring closely matches that of the phenyl ring of bound SCH28080 and aligns between cys120 (TM1), leu141 (TM2) and met334 (TM4), the latter of which is substituted with isoleucine in the Na+,K+ATPase and could also play a role in inhibitor selectivity. There are differences in the two ion pumps, however, that imply that more subtle changes in conformation could affect binding that are not likely to be a function of the residues in direct contact with the inhibitor. Allosteric effects on SCH28080 affinity originating at the ion site have been shown by mutation of lys791 to serine, the amino acid substituted in the Na+,K+-ATPase. A 20fold decrease in affinity was observed for this mutant, suggesting an indirect effect on the structure of the vestibule. A similar mechanism could affect vonoprazan binding or exit from the vestibule. These modelling studies may at least partially explain the specificity of vonoprazan for the H+,K+-ATPase and the reversibility of inhibitor binding, which both have significant implications for the clinical use of this drug. The predicted position and orientation for vonoprazan was tested with AutoDockVina as done for SCH28080. All of the unfixed bonds of the inhibitor were allowed free rotation during the docking analysis. A very similar position was found by AutoDockVina as the best binding pose for vonoprazan, although the pyridine ring was rotated approximately 180⁰ (Figure 6c, stick, carbons in light blue). This finding supports the orientation and placement of vonoprazan derived from both the experimental results and the similarity of its surface envelope compared to that of SCH28080. In summary, this molecular model is clinically relevant because it provides a structural explanation for the specificity, long duration of action and slow reversibility of inhibitor binding, all factors significant for understanding of the mechanism of action of a drug with promise for improved clinical efficacy.
DISCUSSION The burden of acid-related diseases is clinically significant worldwide, and inhibition of acid secretion is the major unifying therapy for these conditions.28 While Aliment Pharmacol Ther 2015; 42: 1315–1326 ª 2015 John Wiley & Sons Ltd
PPIs have gained global acceptance for their role in treating acid-related diseases, there are limitations to their use. PPIs require specific timing of doses with meals, take several days to reach full effect due to the need to reach a steady state of pump turnover and inhibition, are not ideal for preventing night-time acid breakthrough, and have inconsistent effects based on individual patients’ CYP2C19 status.29, 30 The PCABs have been studied extensively as a potential alternative to overcome the limitations of available PPIs. PCABs provide fast onset of action, do not require specific timing with food, and are not metabolised by CYP2C19, allowing for less variability between patients.30, 31 The specific benefits of vonoprazan compared to other drugs in this class include slow dissociation from the H+K+-ATPase, providing longer duration of action, and lack of the hepatotoxicity, due to absence of the imidazopyridine ring, that has limited the clinical application of other PCABs.12, 15, 32, 33 Understanding the mechanism of binding of vonoprazan to the H+,K+-ATPase provides novel insight into its clinical efficacy and a framework for continued development of improved compounds for treatment of acid-related disease. As shown here for both gastric glands and parietal cells, vonoprazan binding is independent of acid secretion and is quite evident after 30 min. This is in contrast to omeprazole binding, that is increased by where there is a 50% increase in the mean number of silver grains in acid-secreting parietal cells when compared to nonsecreting parietal cells.18 In addition, it is clear that the uptake seen in gastric glands is due to binding to the H+,K+ATPase and not due to pH-dependent accumulation in the active secretory canaliculus. Accumulation and acid activation are required for the action of the PPIs but are not required for the action of vonoprazan. Onset of inhibition of acid secretion is therefore effective for both active and resting pumps and does not change with repeated dosing.17 Furthermore, as vonoprazan is acid stable, no gastro-protective coating is required. Human testing has shown that once daily dosing with 40 mg is sufficient to maintain intragastric pH >5.0 over 24 h,17 a level of inhibition not achieved by b.i.d. dosing with any PPI.34 A binding site orientation for vonoprazan has been proposed previously that differs significantly from the one predicted here.35 In the reported binding simulation, an initial homology structure for the H+,K+-ATPase was based on the Na+,K+-ATPase in the E2P state, pdb.2zxe, then used for molecular dynamics in the presence of 1323
D. R. Scott et al. various inhibitors including vonoprazan. Each of the final structures showed a large RMS deviation (~3.0 A) in the overall backbone coordinates compared to the initial structure and an even greater deviation in the luminal vestibule, whose confirmation was further dependent on the inhibitor used for the simulation. The final structure for protonated vonoprazan showed only peripheral interaction of ala335 and tyr799 with the distal end of the pyridine ring, thus not accounting for the dramatic effect of mutating these residues. The effects of various additions or substitutions on the pyridine and fluorophenyl rings have been reported.32 The results given by these modifications can be interpreted by this binding model. In particular, substitution by methoxy in the sixth position of the pyridine ring (Figure 6b, red circle) gives retention of inhibition, and there is space to tolerate this modification in the proposed binding mode. In contrast, there is more than a 100-fold loss of affinity given by replacement of the 2fuoro group with 2-methoxy, and the model suggests the reason is likely steric conflict with L809 (Figure 6b, blue circle). SCH28080 shows 20-fold lower apparent binding affinity than vonoprazan and a much more rapid rate of dissociation.8, 15 The binding affinity predicted by AutoDockVina for vonoprazan was only twofold greater than for SCH28080, and the fourfold difference in the calculated logD values for SCH28080 and vonoprazan (2.69 and 0.56 respectively) also do not support the difference in hydrophobicity as an explanation for the higher affinity of vonoprazan. The occluded appearance of the bound inhibitors (Figures 5 and 6) suggests a possible mechanism in which exit from the binding site is more hindered for vonoprazan. A higher total surface area and a higher percentage of vonoprazan is buried compared to SCH28080, showing that vonoprazan fills the vestibular space more efficiently than SCH28080. In addition, its tight curvature around ala335 (Figure 6b), hydrogen bonding of its methylamino group to the backbone of TM5, and energetically unfavourable passage of the sulfonyl group across the electrostatic barrier presented by asp137 and asn138 (Figure 6b,c) all contribute to the slower rate of dissociation measured for vonoprazan compared to SCH28080 and account for the higher affinity. The presence of the sulfonyl group suggests that ala137 and
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asn138 present a more significant barrier to dissociation of vonoprazan as compared to SCH28080. This model will be useful in designing other K+ competitive inhibitors of the gastric ATPase and predicting selectivity as compared to the Na+,K+ or SERCA ATPases. Development of a more useful and accurate model for binding of vonoprazan is timely as the medication is coming into clinical use.36 Safety in humans was confirmed by phase I studies conducted in Japan and the United Kingdom, looking both at single dose and consecutive dose regimens, with minimal adverse effects noted and lack of sensitivity to CYP2C19 polymorphism.17, 37 Consistent with the data shown here regarding binding and dissociation of vonoprazan, onset of action was seen within 24 h, pH >4 was sustained over the treatment period in most patients including overnight, and tolerance to the drug was not seen.17, 37 Vonoprazan provided more rapid and sustained inhibition of acid secretion when compared directly with two different PPIs in a Japanese population with rapid PPI metaboliser genotype.38 Vonoprazan was also shown to be clinically efficacious and non-inferior to PPIs for the treatment of erosive oesophagitis, a condition that requires sustained acid suppression for healing.39, 40 The acid-independent binding of vonoprazan and the slow dissociation as shown here by labelling of rabbit gastric glands and molecular modelling demonstrate the mechanisms behind these promising clinical results. The relative efficacy of similar PCABs suggests that, provided safety concerns are met, PCAB treatment of gastric acidrelated diseases might replace the use of PPIs.
AUTHORSHIP Guarantor of the article: David R. Scott. Author contributions: EAM, DRS, NWGL and KBM performed the research, collected and analysed the data, designed the research study and wrote the paper, GS designed the study and wrote and edited the manuscript. All authors approved the final version of the article, including the authorship list. ACKNOWLEDGEMENTS Declaration of personal interests: None. Declaration of funding interests: The study was supported by K08DK100661 (EAM), UCLA CDI (EAM), USVA 2I01BX001006 (GS), R01DK105156-01(GS).
Aliment Pharmacol Ther 2015; 42: 1315–1326 ª 2015 John Wiley & Sons Ltd
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