IN SILICO STUDIES ON FUNCTIONALIZED AZAGLYCINE DERIVATIVES CONTAINING 2, 4-THIAZOLIDINEDIONE SCAFFOLD ON MULTIPLE TARGETS
DOI:
https://doi.org/10.22159/ijpps.2017v9i8.19835Keywords:
Functionalized aza glycine, 2, 4-thiazolidinediones, Molecular docking, human immuno deficiency virus-1 protease (HIV-1)Abstract
Objective: The 2, 4-thiazolidinedione containing compounds could lead to most promising scaffolds with higher efficiency toward the targets recognized for its antidiabetic activity when combined with azaglycine moiety. The objective of the present work was to merge functionalized aza glycines with 2, 4-thiazolidinediones, perform in silico evaluation by molecular properties prediction and undertake the molecular docking studies with targets relevant to diabetes, bacterial and viral infections using Swiss Dock programme for unraveling the target identification which can be used for further designing.
Methods: (i) In silico studies were performed using Molinspiration online tool, Swiss ADME website and Swiss Target Prediction websites to compute the physicochemical descriptors, oral bioavailability and brain penetration. (ii) Molecular docking studies were performed using Swiss Dock web service for enumeration of binding affinities and assess their biological potentiality.
Results: The results predicted good drug likeness, solubility, permeability and oral bioavailability for the compounds. All the compounds showed good docking scores as compared to the reference drugs. The N-oleoyl functionalized aza glycine derivative demonstrated superior binding properties towards all the studied target reference proteins, suggesting its significance in pharmacological actions.
Conclusion: The binding interactions observed in the molecular docking studies suggest good binding affinity of the oleoyl functionalized aza glycine derivative, indicating that this derivative would be a promising lead for further investigations of anti-viral, anti-inflammatory and anti-diabetic activities.
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Perucca E, Yasothan U, Clincke G, Kirkpatrick P. Lacosamide Nat Rev Drug Discovery 2008;7:973-4.
Shridhar VA, Cecile B, Stables JP, Harold K. Synthesis and structural studies of aza analogues of functionalized amino acids: New anticonvulsant agents. J Am Chem Soc 2001;1475-8.
Xing R, Hanzlik RP. Azapeptides as inhibitors and active site titrants for cysteine proteinases. J Med Chem 1998;41:1344-51.
Sussans S, Dagan A, Biotnik S, Bialer M. The structural requirement for the design of antiepileptic glycine derivatives. Epilepsy Res 1999;34:207-20.
Molina JM, Villanueva JA, Echevarria J, Chetchotisakd P, Corral J, David N, et al. Efficacy and safety of once-daily atazanavir/ritonavir compared to twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine in ARV-naïve HIV-1-infected subjects: the CASTLE study, 48-week results. 15th conference on retroviruses and opportunistic infections. Boston Abstract 2010;53:323-32.
Malik S, Upadhyaya P, Miglani S. Thiazolidinediones: a plethro of biological load. Int J Pharm Tech Res 2011;3:62-75.
Li Y, Qi Y, Huang T, Yamahara J, Roufogalis B. Pomagranate flower: a unique traditional antidiabetic medicine with dual PPAR alpha/gamma activator properties. Diabetes Obes Metab 2008;10:10-7.
Gaonkar SL, Namratha B, Nitinkumar S, Shimizu H. Microwave-assisted synthesis and evaluation of N-substituted thiazolidine-2,4-dione derivatives as antimicrobial agents. Interactive Med Chem 2014;2:1-5.
Likhar R, Perumal P, Kolhe N, Bhaskar VH, Daroi P. Synthesis and antioxidant activity novel 2-aryl are substituted benzothiazole derivatives. Int J Curr Pharm Res 2015;7:34-7.
Gu MX, Liu XC, Jiang L. Effect of peroxisome proliferator-activated receptor-gamma on proliferation of airway smooth muscle cells in mice with asthma. Chin J Contemp Pediatr 2013;15:583-7.
Ekins S, Rose J. In silico ADME/TOX: The state of the art. J Moll Graphics Model 2002;20:305-9.
Grosdidier A, Zoete V, Michielin O. Eadock: docking of small molecules into protein active sites with a multi objective evolutionary optimization. Proteins 2007;67:1010-25.
Grosdidier A, Zoete V, Michielin O. Swiss Dock, a protein-small molecule docking web service based on EAdock DSS. Nucleic Acids Res 2011;39:W270-7.
Ertl P, Rohde B Selzer P. Fast calculation of molecular polar surface area as a sum of fragment-based contributions and its application to the prediction of drug transport properties. J Med Chem 2000:43:714–7.
Haberthur U, Caflisch A. FACTS: fast analytical continuum treatment of solvation. J Comput Chem 2008;29:701-5.
Veber DF, Johnson SR, Cheng HY, Smith BR, Ward KW, Kopple KD. Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem 2002;45:2615–23.
Petersen EF, Goddard TD, Huang CC, Couch GS, Greenblat DM, Meng EC, et al. UCSF chimera-a visualization system for exploratory research and analysis. J Comput Chem 2004; 13:1605-12.
David G, Grosdidier A, Matthias W, Daina A, Olivier M, Zoete V. Swiss target prediction: a web server for target prediction of bioactive small molecules. Nucleic Acids Res 2014; S42(W1):W32-W38.
Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Delivery Rev 2001;46:3–26.
Lipinski CA. Lead-and drug-like compounds: the rule-of-five revolution. Drug Discovery Today Technologies 2004;1:337–41.
Ghose AK, Viswanadhan VN, Wendoloski JJ. A knowledge-based approach in designing combinatorial or medicinal chemistry libraries for drug discovery. A qualitative and quantitative characterization of known drug databases. J Comb Chem 1999;1:55–68.
Tian S, Wang J, Li Y, Li D, Xu L, Hou T. The application of in silico drug-likeness predictions in Pharmaceutical research. Adv Drug Delivery Rev 2015;86:2-10.
Daina A, Zoete V. A boiled-egg to predict gastrointestinal absorption and brain penetration of small molecules. Chem Med Chem 2016;11:1117-21.
Louis J, Dyda F, Nashed NT, Kimmel AR, Davies DR. Hydrophilic peptides derived from the transframe region of Gag-Pol inhibit the HIV-1 protease. Biochemistry 1998;37:2105-10.
Vijay MK, Premlata KA, Jitender Verma, Mushtaque SS, Raghuvir R, Pissurlenkar S, Evans CC. Molecular docking and 3D-QSAR studies of HIV-1 protease inhibitors. J Med Model 2010;16:1251-68.
Margolin N, Raybuck SA, Wilson KP, Chen W, Fox T, Gu Y, et al. Substrate and inhibitor specificity of interleukin-1β-converting enzyme and related caspases. J Biol Chem 2007;272:7223-8.
Okamoto Y, Anan H, Nakai E, Morihira K, Yonetoku Y, Kurihara H, et al. Peptide based interleukin-1 beta converting enzyme (ICE) inhibitors: synthesis, structure activity relationships and crystallographic study of the ICE-inhibitor complex. Chem Pharm Bull 1999;47:11-21.
Kersten S, Seydoux J, Peters JM, Gonzalez FJ, Desvergne B, Wahli W. Peroxisome proliferator-activated receptor alpha mediates the adaptive response to fasting. J Clin Invest 1999;103:489-98.
Dreyer C, Krey G, Keller H, Givel F, Helftenbein G, Wahli W. Control of the Peroxisomal beta oxidation pathway by a novel family of nuclear hormone receptors. Cell 1992:68:879-87.
Nolte RT, Wisely GB, Westin S, Cobb JE, Lambert MH, Kurokawa R, et al., Ligand binding and co-activator assembly of the Peroxisome proliferator-activated receptor-gamma. Nature 1998;395:137-43.
Jeyam M, Priyadharsini K, Ravikumar P, Shalini G. Evaluating multi target efficiency of phyto compounds against diabetes mellitus-an in silico approach. Bio Info Drug Targets 2014;2:24-8.
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