In silico Molecular Docking and ADME Studies of 1,3,4-Thiadiazole Derivatives in Relation to in vitro PON1 Activity

Author(s): Belgin Sever , Kaan Kucukoglu , Hayrunnisa Nadaroglu , Mehlika Dilek Altıntop* .

Journal Name: Current Computer-Aided Drug Design

Volume 15 , Issue 2 , 2019

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Graphical Abstract:


Background: Paraoxonase 1 (PON1) is a paraoxonase, arylesterase and lactonase associated with protection of lipoproteins and cell membranes against oxidative modification.

Objective: Based on antioxidative properties of PON1 and significance of 1,3,4-thiadiazoles in pharmaceutical chemistry, herein we aimed to evaluate the potentials of 1,3,4-thiadiazole derivatives as PON1 activators.

Methods: 2-[[5-(2,4-Difluoro/dichlorophenylamino)-1,3,4-thiadiazol-2-yl]thio]acetophenone derivatives (1-18) were in vitro evaluated for their activator effects on PON1 which was purified using ammonium sulfate precipitation (60-80%) and DEAE-Sephadex anion exchange chromatography. Molecular docking studies were performed for the detection of affinities of all compounds to the active site of PON1. Moreover, Absorption, Distribution, Metabolism and Excretion (ADME) properties of all compounds were also in silico predicted. In silico molecular docking and ADME studies were carried out according to modules of Schrodinger’s Maestro molecular modeling package.

Results: All compounds, particularly compounds 10, 13 and 17, were determined as promising PON1 activators and apart from compound 1, all of them were detected in the active site of PON1. Besides, ADME results indicated that all compounds were potential orally bioavailable drug-like molecules.

Conclusion: PON1 activators, compounds 10, 13 and 17 stand out as potential drug candidates for further antioxidant studies and these compounds can be investigated for their therapeutic effects in many disorders such as atherosclerosis, diabetes mellitus, obesity, chronic liver inflammation and many more.

Keywords: Paraoxonase 1, thiadiazole, molecular docking, ADME, antioxidant activity, PON1 activators.

Costa, L.G.; Giordano, G.; Cole, T.B.; Marsillach, J.; Furlong, C.E. Paraoxonase 1 (PON1) as a genetic determinant of susceptibility to organophosphate toxicity. Toxicology, 2013, 307, 115-122.
Furlong, C.E.; Suzuki, S.M.; Stevens, R.C.; Marsillach, J.; Richter, R.J.; Jarvik, G.P.; Checkoway, H.; Samii, A.; Costa, L.G.; Griffith, A.; Roberts, J.W.; Yearout, D.; Zabetian, C.P. Human PON1, a biomarker of risk of disease and exposure. Chem. Biol. Interact., 2010, 187(1-3), 355-361.
Kulka, M. A review of paraoxonase 1 properties and diagnostic applications. Pol. J. Vet. Sci., 2016, 19(1), 225-2324.
Shekhanawar, M.; Shekhanawar, S.M.; Krisnaswamy, D.; Indumati, V.; Satishkumar, D.; Vijay, V.; Rajeshwari, T.; Amareshwar, M. The role of ‘paraoxonase-1 activity’ as an antioxidant in coronary artery diseases. J. Clin. Diagn. Res., 2013, 7(7), 1284-1287.
Efrat, M.; Aviram, M. Macrophage paraoxonase 1 (PON1) binding sites. Biochem. Biophys. Res. Commun., 2008, 376(1), 105-110.
Rosenblat, M.; Vaya, J.; Shih, D.; Aviram, M. Paraoxonase 1 (PON1) enhances HDL-mediated macrophage cholesterol efflux via the ABCA1 transporter in association with increased HDL binding to the cells: A possible role for lysophosphatidylcholine. Atherosclerosis, 2005, 179(1), 69-77.
Soran, H.; Younis, N.N.; Charlton-Menys, V.; Durrington, P. Variation in paraoxonase-1 activity and atherosclerosis. Curr. Opin. Lipidol., 2009, 20(4), 265-274.
Costa, L.G.; Giordano, G.; Cole, T.B.; Marsillach, J.; Furlong, C.E. Paraoxonase 1 (PON1) as a genetic determinant of susceptibility to organophosphate toxicity. Toxicology, 2013, 307, 115-122.
Ceron, J.J.; Tecles, F.; Tvarijonaviciute, A. Serum paraoxonase 1 (PON1) measurement: an update. BMC Vet. Res., 2014, 10, 74.
Aviram, M.; Vaya, J. Paraoxonase 1 activities, regulation, and interactions with atherosclerotic lesion. Curr. Opin. Lipidol., 2013, 24(4), 339-344.
Aviram, M.; Rosenblat, M. Paraoxonases 1, 2, and 3, oxidative stress, and macrophage foam cell formation during atherosclerosis development. Free Radic. Biol. Med., 2004, 37(9), 1304-1316.
Meek, E.C.; Chambers, H.W.; Pringle, R.B.; Chambers, J.E. The effect of PON1 enhancers on reducing acetylcholinesterase inhibition following organophosphate anticholinesterase exposure in rats. Toxicology, 2015, 336, 79-83.
Shawali, A.S. 1,3,4-Thiadiazoles of pharmacological interest: Recent trends in their synthesis via tandem 1,3-dipolar cycloaddition. Review J. Adv. Res., 2014, 5(1), 1-17.
Haider, S.; Alam, M.S.; Hamid, H. 1,3,4-Thiadiazoles: A potent multi targeted pharmacological scaffold. Eur. J. Med. Chem., 2015, 92, 156-177.
Matysiak, J. Biological and pharmacological activities of 1,3,4-thiadiazole based compounds. Mini Rev. Med. Chem., 2015, 15(9), 762-775.
Dwivedi, J.; Kaur, N.; Kishore, D.; Kumari, S.; Sharma, S. Synthetic and biological aspects of thiadiazoles and their condensed derivatives: An overview. Curr. Top. Med. Chem., 2016, 16(26), 2884-2920.
Frija, L.M.T.; Pombeiro, A.J.L.; Kopylovich, M.N. Coordination chemistry of thiazoles, isothiazoles and thiadiazoles. Coord. Chem. Rev., 2016, 308, 32-55.
Aliabadi, A. 1,3,4-Thiadiazole based anticancer agents. Anticancer. Agents Med. Chem., 2016, 16(10), 1301-1314.
Akhtar, J.; Khan, A.A.; Ali, Z.; Haider, R.; Shahar Yar, M. Structure-activity relationship (SAR) study and design strategies of nitrogen-containing heterocyclic moieties for their anticancer activities. Eur. J. Med. Chem., 2017, 125, 143-189.
Hu, Y.; Li, C.Y.; Wang, X.M.; Yang, Y.H.; Zhu, H.L. 1,3,4-Thiadiazole: Synthesis, reactions, and applications in medicinal, agricultural, and materials chemistry. Chem. Rev., 2014, 114(10), 5572-5610.
Altintop, M.D.; Ozdemir, A.; Kucukoglu, K.; Turan-Zitouni, G.; Nadaroglu, H.; Kaplancikli, Z.A. Synthesis and evaluation of new thiadiazole derivatives as potential inhibitors of human carbonic anhydrase isozymes (hCA-I and hCA-II). J. Enzyme Inhib. Med. Chem., 2015, 30(1), 32-37.
Harel, M.; Aharoni, A.; Gaidukov, L.; Brumshtein, B.; Khersonsky, O.; Meged, R.; Dvir, H.; Ravelli, R.B.; McCarthy, A.; Toker, L.; Silman, I.; Sussman, J.L.; Tawfik, D.S. Structure and evolution of the serum paraoxonase family of detoxifying and anti-atherosclerotic enzymes. Nat. Struct. Mol. Biol., 2004, 11(5), 412-419.
Demir, Y.; Nadaroglu, H.; Demir, N. Effect of glimepride on paraoxanase activity. Pharm. Biol., 2006, 44(5), 396-399.
Renault, F.; Chabriѐre, E.; Andrieu, J.; Dublet, B.; Massona, P.; Rochua, D. Tandem purification of two HDL-associated partner proteins in human plasma, paraoxonase (PON1) and phosphate binding protein (HPBP) using hydroxy apatite chromatography. J. Chromatogr. B ., 2006, 836, 15-21.
Demir, N.; Nadaroglu, H.; Demir, Y. Purification of human serum paraoxonase and effect of acetylsalicylic acid on paraoxonase activity. Pharm. Biol., 2008, 46(6), 393-399.
Bradford, M.M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dyebinding. Anal. Biochem., 1976, 72, 248.
Laemmli, U.K. Cleavage of the structural proteins during the assembly of the head of bacteriophage T4. Nature, 1970, 227(229), 680-685.
Sinan, S.; Kockar, F.; Arslan, O. Novel purification strategy for human PON1 and inhibition of the activity by cephalosporin and aminoglikozide derived antibiotics. Biochimie, 2006, 88, 565-574.
Alici, H.A.; Ekinci, D.; Beydemir, Ş. Intravenous anesthetics inhibit human paraoxonase-1 (PON1) activity in vitro and in vivo. Clin. Biochem., 2008, 41, 1384-1390.
Dilek, E.B.; Küfrevioğlu, Ö.İ.; Beydemir, Ş. Impacts of some antibiotics on human serum paraoxonase 1 activity. J. Enzyme Inhib. Med. Chem., 2013, 28(4), 758-764.
Ekinci, D.; Beydemir, Ş. Evaluation of the impacts of antibiotic drugs on PON 1; a major bioscavenger against cardiovascular diseases. Eur. J. Pharmacol., 2009, 617(1-3), 84-89.
Akbaba, Y.; Türkeş, C.; Polat, L.; Söyüt, H.; Şahin, E.; Menzek, A.; Göksu, S.; Beydemir, Ş. Synthesis and paroxonase activities of novel bromophenols. J. Enzyme Inhib. Med. Chem., 2013, 28(5), 1073-1079.
Tavori, H.; Khatib, S.; Aviram, M.; Vaya, J. Characterization of the PON1 active site using modeling simulation, in relation to PON1 lactonase activity. Bioorg. Med. Chem., 2008, 16(15), 7504-7509.
Van Den Driessche, G.; Fourches, D. Adverse drug reactions triggered by the common HLA-B*57:01 variant: A molecular docking study. J. Cheminform., 2017, 9, 13.
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.
Jorgensen, W.L.; Duffy, E.M. Prediction of drug solubility from structure. Adv. Drug Deliv. Rev., 2002, 54, 355-366.
Frecer, V.; Berti, F.; Benedetti, F.; Miertus, S. Design of peptidomimetic inhibitors of aspartic protease of HIV-1 containing –PheψPro– core and displaying favourable ADME-related properties. J. Mol. Graph. Model., 2008, 27, 376-387.

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Article Details

Year: 2019
Page: [136 - 144]
Pages: 9
DOI: 10.2174/1573409914666180518085908
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