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Extra precision glide docking, free energy calculation and molecular dynamics studies of 1,2-diarylethane derivatives as potent urease inhibitors

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Abstract

For the latter half of the twentieth century, most medical professionals considered bacterial infection to be a primary cause of gastrointestinal ulcers in human beings. In 1994, the World Health Organization (WHO) recognized Helicobacter pylori, the bacterium most closely linked to ulcer development, as a type I carcinogen. Biological research has shown that there is a positive correlation between the number of species in the Helicobacter genus and the number of medical conditions associated with Helicobacter infection, both of which are increasing rapidly. N-Benzylaniline derivatives, frequently used in industrial manufacturing, are being considered as a strong candidate for ongoing drug modeling in search of novel therapies. The basic goal behind this study was to determine the potency of experimentally proved data, and to determine favorable substituents to enhance potency, and thereafter to support this finding through theoretical modification of the existing base skeleton by addition of suitable substituents. Ligands were investigated thoroughly by paying attention to the urease-inhibitory properties present in the selected series. Initially, docking was performed on ligands with protein to produce efficient docking poses. Molecular dynamics (MD) simulations were also performed to precisely understand the interactions between ligands and proteins. Thereafter, MM-GBSA was used in order to validate the methods and results. Good interaction was observed with amino acids Arg338, Ala169, Asp223, His322, and Asn168. This study also revealed that the electron rich hydroxyl group (–OH) substituent plays an important role during bond formation. In addition, various hydrogen bonds, ionic bonds, and pi–pi stacking bonds make significant contributions towards urease inhibition. Therefore, further research utilizing electron-rich moieties may lead to novel and efficacious urease inhibitors.

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References

  1. Marshall BJ (1983) Unidentified curved bacilli on gastric epithelium in active chronic gastritis. Lancet 1:1273–1275

    PubMed  Google Scholar 

  2. Blaser MJ (1990) Helicobacter pylori and the pathogenesis of gastro duodenal inflammation. J Infect Dis 161:626–633

  3. Kitahara F, Shimazaki R, Sato T, Kojima Y, Morozumi A, Fujino MA (1998) Severe atrophic gastritis with Helicobacter pylori infections and gastric cancer. Gastric Cancer 1:118–124

    Article  PubMed  Google Scholar 

  4. Kusters JG, Van Vliet AHM, Kuipers EJ (2006) Pathogenesis of Helicobacter pylori infection. Clin Microbial Rev 19:449–490

    Article  CAS  Google Scholar 

  5. Shokerzadeh L, Baqhaei K, Yamaoka Y, Dabiri H, Jafari F, Sahebekhtiari N, Tahami A, Suqianoto M, Zoiaji H, Zali MR (2010) Analysis of 3-end variable region of the caga gene in Helicobacter pylori isolated from Iranian population. J Gastroenterol Hepatol 25:172–177

    Article  CAS  Google Scholar 

  6. Hołubiuk Ł, Imiela J (2016) Diet and Helicobacter pylori infection. Prz Gastroenterol 11:150–154

    Article  PubMed  PubMed Central  Google Scholar 

  7. Joseph IM, Kirschner D (2004) A model for the study of Helicobacter pylori interaction with human gastric acid secretion. J Theore Bio 228:55–80

    Article  CAS  Google Scholar 

  8. H. pylori Transmission and spread of infection. Mel and Enid Zuckerman College of Public Health. Available at: https://publichealth.arizona.edu/outreach/health-literacy-awareness/hpylori/transmission. [Accessed 28 August 2017]

  9. Abdullah MA, Abuo-Rahma GE, Abdelhafez EM (2017) Design, synthesis, molecular docking, anti-Proteus mirabilis and urease inhibition of new fluoroquinolone carboxylic acid derivatives. Bioorg Chem 70:1–11

    Article  CAS  PubMed  Google Scholar 

  10. Kafarski P, Talma M (2018) Recent advances in design of new urease inhibitors: a review. J Adv Res 13:101–112

  11. Hassan STS, Sudomova E (2017) Biological evaluation and molecular docking of protocatechuic acid from Hibiscus sabdariffa L. as a potent urease inhibitor by an ESI-MS based method. Molecule 22:1696

    Article  CAS  Google Scholar 

  12. Zaborska W, Krajewska B, Kot M, Karcz W (2007) Quinone-induced inhibition of urease: elucidation of its mechanisms by probing thiol groups of the enzyme. Bioorg Chem 35:233–242

    Article  CAS  PubMed  Google Scholar 

  13. Schaffer JN, Melanie M (2015) Pearson, Proteus mirabilis and urinary tract infection. Microbial Spetr 5. https://doi.org/10.1128/microbiolspec.UTI-0017-2013

  14. Hovelius B, Mardh PA (1984) Staphylococcus saprophyticus as a common cause of urinary tract infections. Rev Infect Dis 6:328–337

    Article  CAS  PubMed  Google Scholar 

  15. Mobley HLT (2001) Urease. In: Mendz GL, Hazell SL (eds) Helicobacter pylori: Physiology and genetics, chapter 16. ASM, Washington DC

  16. Hawtin PR, Delves HT, Newell DG (1991) The demonstration of nickel in the urease of Helicobacter pylori by atomic absorption spectroscopy. FEMS Microbiol Lett 77:51–54

    Article  CAS  Google Scholar 

  17. Hausinger RP (1987) Nickel utilization by microorganism. Microbial Rev 51:22–24

    CAS  Google Scholar 

  18. Han SY et al. (2003) N-Benzylideneaniline and N-Benzylaniline are potent inhibitors of Lignostilbene-α,β-dioxygenase, a key enzyme in oxidative cleavage of the central double bond of Lignostilbene 18: 279–283

  19. Brooks BR, Bruccoleri RE, Olafson BD, States DJ, Swaminathan S, Karplus M (1983) Charmm, A program for macromolecular energy, minimization and dynamics calculations. J Comput Chem 4:187–217

    Article  CAS  Google Scholar 

  20. Cornell WD, Cieplak P, Bayly CL, Gould IR, Merz KM, Ferguson DM, Spellmeyer DC, Fox T, Caldwell JW, Kollman PA (1995) A second generation force field for the simulation of proteins, nuclic acids, and organic molecules. J Am Chem Soc 117:5179–5197

    Article  CAS  Google Scholar 

  21. Ensor KB, Glynn PW (1996) Grid–based simulation and the method of Conditional Least Squares. In: Charnes JM, Morrice DJ, Brunner DT, Swain JJ (eds) Proceedings of the 1996 Winter Simulation Conference. IEEE, Piscataway NJ, pp 325–331

  22. Still WC, Tempczyle A, Hawley RC, Hendrickson T (1990) Semianalytical treatment of salvation for molecular mechanics and dynamics. J Am Chem Soc 16:6127–6129

    Article  Google Scholar 

  23. Schrödinger Release 2017-1 (2017) LigPrep, Schrödinger. LLC, New York, NY

    Google Scholar 

  24. Xiao ZP, She WK et al. (2015) Synthesis and evaluation N-analogs of 1,2-diarylethane as Helicobacter pylori urease inhibition 23: 4508–4513

  25. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE (2000) The Protein Data Bank. Nucleic Acids Res 28:235–242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Sastry GM, Adzhigirey M, Day T, Annabhimoju R, Sherman W (2013) Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments. J Comput Aid Mol Des 27:221–234

    Article  CAS  Google Scholar 

  27. Shivakumar D, Williams J, Wu Y, Damm W, Shelley J, Sherman W (2010) Prediction of absolute solvation free energies using molecular dynamics free energy perturbation and the OPLS force field. J Chem Theory Comput 6:1509–1519

    Article  CAS  PubMed  Google Scholar 

  28. Ferrari AM, Egliesposti G, Sqobba M, Rastelli G (2007) Validation of an automated procedure for the prediction of relative free energies of binding on a set of aldose reductase inhibitors. Bioorg Med Chem 24:7865–7877

  29. Kurczab R (2017) The evaluation QM/MM-driven molecular docking combined with MM/GBSA calculations as a halogen bond scoring strategy. Acta Cryst 73:188–194

    CAS  Google Scholar 

  30. Alexander DLJ, Tropsha A, Winkler DA (2015) Beware of R2: simple, unambiguous assessment of the prediction accuracy of QSAR and QSPR models. J Chem Inf Model 55:1316–1322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Besalu E, de Julian-Ortiz JV, Poqliani L (2007) Trends and plot methods in MLR studies. J Chem Inf Model 47:751–760

    Article  CAS  PubMed  Google Scholar 

  32. Jain AN (2008) Bias, reporting, and sharing: computational evaluations of docking methods. J Comput Aided Mol Des 22:201–212

    Article  CAS  PubMed  Google Scholar 

  33. Oliviero C, Sandor P (2001) A normalized root-mean-square distance for comparing protein three-dimensional structures. Protein Sci 7:1470–1473

    Google Scholar 

  34. Rui-guang GE, Dong-Xian W, Minq-conq H, Xue-song S (2013) Nickel trafficking system responsible for urease maturation in Helicobacter pylori. World J Gastroenterol 45:8211–8218

  35. Correlation Coefficients (2017) Correlation coefficients. [ONLINE] availability: https://www.andrews.edu/~calkins/math/edrm611/edrm05.htm. [Accessed 31 August 2017]

  36. Xiaoqian Z, Xin L, Xiaodong J, Xiangfei M, Jinghua F (2012) The performance analysis of massively parallel program NAMD on th-1A. In: Zeng D (ed) Advances in information technology and industry applications, vol 136. Springer, Berlin, pp 265–270

    Chapter  Google Scholar 

  37. National Institute of Diabetes and Digestive and Kidney Diseases (2017) Gastritis. NIDDK. Available at: https://www.niddk.nih.gov/health-information/digestive-diseases/gastritis. [Accessed 28 August 2017]

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Author notes

  1. Sheetal Gupta and A. V. Bajaj contributed equally to this work.

Authors and Affiliations

  1. School of Chemical Sciences, Devi Ahilya Vishvavidyalaya, Takshashila Campus, Khandwa Road, Indore, India

    Sheetal Gupta & A. V. Bajaj

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  1. Sheetal Gupta
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  2. A. V. Bajaj
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Correspondence to Sheetal Gupta.

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Gupta, S., Bajaj, A.V. Extra precision glide docking, free energy calculation and molecular dynamics studies of 1,2-diarylethane derivatives as potent urease inhibitors. J Mol Model 24, 261 (2018). https://doi.org/10.1007/s00894-018-3787-4

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