Protonated Form: the Potent Form of Potassium-competitive Acid Blockers

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2014 May 22

PMID 24845980

Citations 6

Authors

Hua-Jun Luo

Wei-Qiao Deng

Kun Zou

Affiliations

Soon will be listed here.

Abstract

Potassium-competitive acid blockers (P-CABs) are highly safe and active drugs targeting H+,K+-ATPase to cure acid-related gastric diseases. In this study, we for the first time investigate the interaction mechanism between the protonated form of P-CABs and human H+,K+-ATPase using homology modeling, molecular docking, molecular dynamics and binding free energy calculation methods. The results explain why P-CABs have higher activities with higher pKa values or at lower pH. With positive charge, the protonated forms of P-CABs have more competitive advantage to block potassium ion into luminal channel and to bind with H+,K+-ATPase via electrostatic interactions. The binding affinity of the protonated form is more favorable than that of the neutral P-CABs. In particular, Asp139 should be a very important binding site for the protonated form of P-CABs through hydrogen bonds and electrostatic interactions. These findings could promote the rational design of novel P-CABs.

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References

Vagin O, Denevich S, Munson K, Sachs G . SCH28080, a K+-competitive inhibitor of the gastric H,K-ATPase, binds near the M5-6 luminal loop, preventing K+ access to the ion binding domain. Biochemistry. 2002; 41(42):12755-62. DOI: 10.1021/bi025921w. View

Sali A, Blundell T . Comparative protein modelling by satisfaction of spatial restraints. J Mol Biol. 1993; 234(3):779-815. DOI: 10.1006/jmbi.1993.1626. View

Shin J, Munson K, Vagin O, Sachs G . The gastric HK-ATPase: structure, function, and inhibition. Pflugers Arch. 2008; 457(3):609-22. PMC: 3079481. DOI: 10.1007/s00424-008-0495-4. View

Arikawa Y, Nishida H, Kurasawa O, Hasuoka A, Hirase K, Inatomi N . Discovery of a novel pyrrole derivative 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine fumarate (TAK-438) as a potassium-competitive acid blocker (P-CAB). J Med Chem. 2012; 55(9):4446-56. DOI: 10.1021/jm300318t. View

Hall K, Perez G, Anderson D, Gutierrez C, Munson K, Hersey S . Location of the carbohydrates present in the HK-ATPase vesicles isolated from hog gastric mucosa. Biochemistry. 1990; 29(3):701-6. DOI: 10.1021/bi00455a016. View

Li H, Meng L, Liu F, Wei J, Wang Y . H+/K+-ATPase inhibitors: a patent review. Expert Opin Ther Pat. 2012; 23(1):99-111. DOI: 10.1517/13543776.2013.741121. View

Shelley J, Cholleti A, Frye L, Greenwood J, Timlin M, Uchimaya M . Epik: a software program for pK( a ) prediction and protonation state generation for drug-like molecules. J Comput Aided Mol Des. 2007; 21(12):681-91. DOI: 10.1007/s10822-007-9133-z. View

Asano S, Matsuda S, Tega Y, Shimizu K, Sakamoto S, Takeguchi N . Mutational analysis of putative SCH 28080 binding sites of the gastric H+,K+-ATPase. J Biol Chem. 1997; 272(28):17668-74. DOI: 10.1074/jbc.272.28.17668. View

Bytzer P . Goals of therapy and guidelines for treatment success in symptomatic gastroesophageal reflux disease patients. Am J Gastroenterol. 2003; 98(3 Suppl):S31-9. DOI: 10.1016/s0002-9270(03)00013-3. View

10.

Humphrey W, Dalke A, Schulten K . VMD: visual molecular dynamics. J Mol Graph. 1996; 14(1):33-8, 27-8. DOI: 10.1016/0263-7855(96)00018-5. View

11.

Friesner R, Murphy R, Repasky M, Frye L, Greenwood J, Halgren T . Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. J Med Chem. 2006; 49(21):6177-96. DOI: 10.1021/jm051256o. View

12.

Matsukawa J, Hori Y, Nishida H, Kajino M, Inatomi N . A comparative study on the modes of action of TAK-438, a novel potassium-competitive acid blocker, and lansoprazole in primary cultured rabbit gastric glands. Biochem Pharmacol. 2011; 81(9):1145-51. DOI: 10.1016/j.bcp.2011.02.009. View

13.

Li W, Yang Y, Tian Y, Xu X, Chen Y, Mu L . Preparation and in vitro/in vivo evaluation of revaprazan hydrochloride nanosuspension. Int J Pharm. 2011; 408(1-2):157-62. DOI: 10.1016/j.ijpharm.2011.01.059. View

14.

Beil W, Hackbarth I, SEWING K . Mechanism of gastric antisecretory effect of SCH 28080. Br J Pharmacol. 1986; 88(1):19-23. PMC: 1917128. DOI: 10.1111/j.1476-5381.1986.tb09466.x. View

15.

Sachs G, Shin J, Vagin O, Lambrecht N, Yakubov I, Munson K . The gastric H,K ATPase as a drug target: past, present, and future. J Clin Gastroenterol. 2007; 41 Suppl 2:S226-42. PMC: 2860960. DOI: 10.1097/MCG.0b013e31803233b7. View

16.

Dent J, Kahrilas P, Hatlebakk J, Vakil N, Denison H, Franzen S . A randomized, comparative trial of a potassium-competitive acid blocker (AZD0865) and esomeprazole for the treatment of patients with nonerosive reflux disease. Am J Gastroenterol. 2008; 103(1):20-6. DOI: 10.1111/j.1572-0241.2007.01544.x. View

17.

Berman H, Westbrook J, Feng Z, Gilliland G, Bhat T, Weissig H . The Protein Data Bank. Nucleic Acids Res. 1999; 28(1):235-42. PMC: 102472. DOI: 10.1093/nar/28.1.235. View

18.

Maeda M, Oshiman K, Tamura S, Futai M . Human gastric (H+ + K+)-ATPase gene. Similarity to (Na+ + K+)-ATPase genes in exon/intron organization but difference in control region. J Biol Chem. 1990; 265(16):9027-32. View

19.

Chenna R, Sugawara H, Koike T, Lopez R, Gibson T, Higgins D . Multiple sequence alignment with the Clustal series of programs. Nucleic Acids Res. 2003; 31(13):3497-500. PMC: 168907. DOI: 10.1093/nar/gkg500. View

20.

Shin J, Inatomi N, Munson K, Strugatsky D, Tokhtaeva E, Vagin O . Characterization of a novel potassium-competitive acid blocker of the gastric H,K-ATPase, 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate (TAK-438). J Pharmacol Exp Ther. 2011; 339(2):412-20. PMC: 3199995. DOI: 10.1124/jpet.111.185314. View