Quantitative Structure-Activity Relationship and Docking Studies on a series of H+/K+-ATPase inhibitors

Basheerulla      Shaik; Satya    Prakash   Gupta; Shweta       Sharma

doi:10.2174/1570178616666190222153819

Abstract

Background: The Gastric H+/K+-ATPase is also known as proton pump is the enzyme responsible for the acidification of gastric juice. H+/K+ GastroEsophageal Reflux Disease (GERD) and other acid related diseases mainly depend on the inhibition of the gastric H+/K+- ATPase which will finally result in acid secretion in stomach. GERD is one of the diseases that have significant effect on the quality of human life and are the major burden on health care systems is that leads to heart burn, acid regurgitation, chest pain, epigastric pain, and respiratory conditions such as chronic cough. Hence the study of the inhibitors of Gastric H+/K+-ATPase is desired.

Methods: Research and online content related to imidazo [1, 2-a]pyrazine and heterocyclic ring analogues (I) that were synthesized and evaluated for their Gastric H+/K+-ATPase inhibitory activity is reviewed, and in order to design and develop still better and more effective H+/K+-ATPase inhibitors, we have made Quantitative Structure Activity Relationship (QSAR), docking and ADMET studies on these compounds.

Results: The best MLR equation based on four descriptors along with statistical parameters is obtained using Statistica dataminer software. Using the model expressed by this study we predicted some new compounds of high H+/K+-ATPase inhibition potency. Each predicted compound has very high potency with which only a few compounds of existing series can match.

Conclusion: The QSAR and molecular modelling studies suggested that still better compounds can be designed if the flexibility of the molecules can be increased for which attempts can be made to have more saturated atoms in the molecules. Such a compound predicted by us was found to have interactions with the enzyme H+/K+-ATPase almost in the same manner as the FDA approved compounds, lansoprazole, pantaprazole.

Keywords: Imidazo[1, 2-a]pyrazine, QSAR, molecular docking, ADMET, Gastroesophageal reflux disease, epigastric pain.

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[1] 
Sakai, H.; Fujii, T.; Takeguchi, N. Proton-potassium (H+/K+)
ATPases: Properties and roles in health and diseases. In Astrid, S.;
Helmut, S.; Roland K.O.S (Eds). . The Alkali Metal Ions: Their Role
in Life. Metal Ions in Life Sciences; , 2016, 16, pp. 459-483.
[2] 
Shin, J.M.; Munson, K.; Vagin, O.; Sachs, G. The gastric HK-ATPase: Structure, function and inhibition. Pflugers Arch.,  2009, 457, 609-622.
[3] 
Berg, J.M.; Tymoczko, J.L.; Stryer, L. Biochemistry ,  ((7th ed.). ), NewYork: W.H. Freeman and Company. 
[4] 
Shin, J.M.; Vagin, O.; Munson, K.; Kidd, M.; Modlin, I.M.; Sachs, G. Molecular mechanisms in therapy of acid-related diseases. Cell. Mol. Life Sci.,  2008, 65, 264-281.
[5] 
Michelle, L. Gumz, M.L.; Lynch, I.J.; Greenlee, M.M.; Cain, B.D.; Wingo, C.S. The renal H+-K+-ATPases: Physiology, regulation, and structure. Am. J. Physiol. Renal Physiol.,  2010, 298, F12-F21.
[6] 
Sachs, G.; Shin, J.M.; Vagin, O. lambrecht, N.; Yacubov, I.; Munson, K. The gastric H,K ATPase as a drug target: Past, present, and future. J. Clin. Gastroenterol.,  2007, 41, S226-S242.
[7] 
Bamford, M.H. +, K+-ATPase inhibitors in the treatment of acid related disorders. Prog. Med. Chem.,  2009, 47, 76-162.
[8] 
Panchal, T.; Bailey, N.; Bamford, M.; Demont, E.; Elliott, R.; Farre-Gutierrez, I.; Garton, N.; Hayhow, T.; Hutley, G.; Naylor, A. Evaluation of basic, heterocyclic ring systems as templates for use as potassium competitive acid blockers (pCABs). Bioorg. Med. Chem. Lett.,  2009, 19, 6813-6817.
[9] 
Zimmermann, P.J.; Brehm, C.; Buhr, W.; Palmer, A.M.; Volz, J.; Simon, W.A. Novel imidazo[1, 2-a]pyrazine derivatives as potent reversible inhibitors of the gastric H+/K+-ATPase. Bioorg. Med. Chem.,  2008, 16, 536-541.
[10] 
Zimmermann, P.J.; Buhr, W.; Brehm, C.; Palmer, A.M.; Feth, M.P.; Bilfinger, J.; Simon, W.A. Novel indanyl-substituted imidazo[1,2-a]pyridines as potent reversible inhibitors of the gastric H+/K+-ATPase. Bioorg. Med. Chem. Lett.,  2007, 17, 5374-5378.
[11] 
Ghose, A.K.; Viswanadhan, V.N.; Wendoloski, J.J. Prediction of hydrophobic (lipophilic) properties of small organic molecules using fragmental methods: An analysis of ALOGP and CLOGP methods. J. Phys. Chem.,  1998, 102, 3762-3772.
[12] 
Ghose, A.K.; Crippen, G.M. Atomic physicochemical parameters for three-dimensional-structure-directed quantitative structure-activity relationships. 2. Modeling dispersive and hydrophobic interactions. J. Chem. Inf. Comput. Sci.,  1987, 27, 21-35.
[13] 
Sander, T.; Freyss, J.; Korff, M.V.; Rufener, C. DataWarrior: An open-source program for chemistry aware data visualization and analysis. J. Chem. Inf. Model.,  2015, 55, 460-473.
[14] 
Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev.,  2001, 46, 3-26.
[15] 
Lipinski, C.A. Lead- and drug-like compounds: The rule-of-five revolution. Drug Discov. Today. Technol.,  2004, 1, 337-341.
[16] 
Abe, K.; Tani, K.; Fujiyoshi, Y. Conformational rearrangement of gastric H+,K+ ATPase induced by an acid suppressant. Nat. Commun.,  2011, 2, 155.
[17] 
Gupta, S.P. Roles of fluorine in drug design and drug action. Lett. Drug Des. Discov.,  2019, 16 in Press
[18] 
Ahmad, I.; Shaik, B.; Singh, N.; Agrawal, V.K.; Anita, K.; Gupta, S.P. Quantitative structure-activity relationship and molecular modeling studies on a series of H+/K+ -ATPase inhibitors. J. Appld. Biophar. Pharmacokinetics.,  2016, 4, 20-39.
[19] 
Agrawal, N.; Bajpai, A.; Srivastava, V.; Gupta, S.P. A quantitative structure activity relationship and molecular modeling study on a series of biaryl imidazole derivatives acting as H+/K+-ATPase inhibitors. Struc. Biol.,  2013, 810691, 11.
[20] 
Agarwal, N.; Bajpai, A.; Gupta, S.P. A quantitative structure-activity relationship and molecular modeling study on a series of heteroaryl- and heterocyclyl-substituted imidazo[1, 2-a]pyridine derivatives acting as acid pump antagonists. Biochem. Res. Int.,  2013, 141469, 15.

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DOI https://dx.doi.org/10.2174/1570178616666190222153819	Print ISSN 1570-1808
Publisher Name Bentham Science Publisher	Online ISSN 1875-628X

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Quantitative Structure-Activity Relationship and Docking Studies on a series of H+/K+-ATPase inhibitors

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