Abstract
The occurrence of type 2 diabetes (T2D) accounts for 90–95 % of all diabetes. Intestine hormone glucagon-like peptide-1 (GLP-1) has an antidiabetic role that enhances insulin secretion and pancreatic β-cell proliferation. GLP-1 is degraded by the enzyme dipeptidyl peptidase-4 (DPP-4) rapidly. Hence, the DPP-4 inhibition has been preferred not only for the treatment but also as a major drug target. Sitagliptin and Diprotin-A are antihyperglycemic agents for the treatment of T2D. However, little is known on the molecular dynamics of DPP-4 and the interaction properties with its ligands, namely Sitagliptin and Diprotin-A. This study has used the latest bioinformatic tools to understand the molecular dynamics and its interaction properties of DPP-4. This study has explored the number of α helices, β strands, β hairpins, Ψ loop, β bulges, β turns, and ϒ turns and they were 19, 46, 25, 1, 14, 70, and 4, respectively. The highest number of H-bonds was recorded in α helix of domain-1, and the lowest number H-bonds were noted in α helix of domain-2. During interaction between residues, in A- and B-chain, 47 and 48 residues are involved for interaction, and interaction interface area was more in A-Chain (2176 Å2). From DPP-4 and Sitagliptin interaction, three residues in active sites such as Try226, Glu205, and Glu206 were involved in three H-bond formation, while 10 other amino acids (Try547, Try667, Asn710, Val711, His740, Ser630, Ser209, Arg358, Phe357, and Val207) were involved in hydrophobic interactions. In this review, we have shown the importance of bioinformatics as an excellent tool for a rapid method to assess the molecular dynamics and its interaction properties of DPP-4. Our predictions highlighted in this review will help researchers to understand the interaction properties and recognition of interactive sites to design more DPP-4 inhibitors for the treatment of T2D and drug discovery.
Similar content being viewed by others
References
Zimmet, P. (2000). Globalization, coca-colonization and the chronic disease epidemic: Can the doomsday scenario be averted? Journal of Internal Medicine, 247, 301–310.
Zimmet, P., Alberti, K. G., & Shaw, J. (2001). Global and societal implications of the diabetes epidemic. Nature, 414, 782–787.
World Diabetes Population Hits 366 Million. (http://www.mydiabetes.in/news/2011/Sep/world-diabetes-population-hits-366-million-91552382.html)
Whiting, D. R., Guariguata, L., Weil, C., & Shaw, J. (2011). IDF diabetes atlas: Global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Research and Clinical Practice, 94, 311–321.
Moller, D. E. (2001). New drug targets for type 2 diabetes and the metabolic syndrome. Nature, 414(6865), 821–827.
Wild, S., Roglic, G., Green, A., Sicree, R., & King, H. (2004). Global preference of diabetes. Diabetes Care, 27, 1047–1053.
Alberti, K. G., & Zimmet, P. Z. (1998). Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: Diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabetic Medicine, 15, 539–553.
Choy, M., & Lam, S. (2007). Sitagliptin: A novel drug for the treatment of type 2 diabetes. Cardiology Reviews, 15, 264–271.
FDA Approves New Treatment for Diabetes (Press release, 2006, October 17). U.S. Food and Drug Administration (FDA). Retrieved October 17, 2006
Herman, G. A., Stevens, C., Van Dyck, K., Bergman, A., Yi, B., et al. (2005). Pharmacokinetics and pharmacodynamics of single doses of sitagliptin, an inhibitor of dipeptidyl peptidase-IV, in healthy subjects. Clinical Pharmacology & Therapeutics, 78, 675–688.
Daniel, D., Chris, E., & Peter, K. (2007). Fresh from the Pipeline: Sitagliptin. Nature Reviews Drug Discovery, 6, 109–110.
Herman, G. A., Stevens, C., & Van Dyck, K. (2005). Pharmacokinetics and pharmacodynamics of sitagliptin, an inhibitor of dipeptidyl peptidase IV, in healthy subjects: results from two randomized, double-blind, placebo-controlled studies with single oral doses. Clinical Pharmacology and Therapeutics, 78, 675–688.
Raz, I., Hanefeld, M., Xu, L., Caria, C., Williams-Herman, D., et al. (2006). Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus. Diabetologia, 49, 2564–2571.
Aschner, P., Kipnes, M. S., Lunceford, J. K., Sanchez, M., Mickel, C., Williams-Herman, D. E., et al. (2006). Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care, 29, 2632–2637.
Charbonnel, B., Karasik, A., Liu, J., Wu, M., Meininger, G., et al. (2006). Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care, 29, 2638–2643.
Rosenstock, J., Brazg, R., Andryuk, P. J., Lu, K., Stein, P., et al. (2006). Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in patients with type 2 diabetes: A 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Clinical Therapeutics, 28, 1556–1568.
Rahfeld, J., Schierhorn, M., Hartrodt, B., Neubert, K., & Heins, J. (1991). Are diprotin A (Ile-Pro-Ile) and diprotin B (Val-Pro-Leu) inhibitors or substrates of dipeptidyl peptidase IV? Biochimica et Biophysica Acta, 1076, 314–316.
Alponti, R. F., Frezzatti, R., Barone, J. M., Alegre, V. S., & Silveiraa, P. F. (2011). Dipeptidyl peptidase IV in the hypothalamus and hippocampus of monosodium glutamate obese and food-deprived rats. Metabolism, 60, 234–242.
Hiramatsu, H., Yamamoto, A., Kyono, K., Higashiyama, Y., Fukushima, C., Shima, H., et al. (2004). The crystal structure of human dipeptidyl peptidase IV (DPPIV) complex with diprotin A. Journal of Biological Chemistry, 385, 561–564.
Deacon, C. F., Ahrén, B., & Holst, J. J. (2004). Inhibitors of dipeptidyl peptidase IV: A novel approach for the prevention and treatment of Type 2 diabetes? Expert Opinion on Investigational Drugs, 13, 1091–1102.
Ahrén, B. (2005). Inhibition of dipeptidyl peptidase-4 (DPP-4)—A novel approach to treat type 2 diabetes. Current Enzyme Inhibition, 1, 65–73.
Drucker, D. J. (2006). The biology of incretin hormones. Cell Metabolism, 3, 153–165.
Baggio, L. L., & Drucker, D. J. (2007). Biology of incretins: GLP-1 and GIP. Gastroenterology, 132, 2131–2157.
Misumi, Y., Hayashi, Y., Arakawa, F., & Ikehara, Y. (1992). Molecular cloning and sequence analysis of human dipeptidyl peptidase IV, a serine proteinase on the cell surface. Biochimica et Biophysica Acta, 1131, 333–336.
Abbott, C. A., Baker, E., Sutherland, G. R., & McCaughan, G. W. (1994). Genomic organization, exact localization, and tissue expression of the human CD26 (dipeptidyl peptidase IV) gene. Immunogenetics, 40, 331–338.
Hong, W., & Doyle, D. J. (1990). Molecular dissection of the NH2-terminal signal/anchor sequence of rat dipeptidyl peptidase IV. Cell Biology, 111, 323–338.
Ludwig, K., Yan, S., Fan, H., Reutter, W., & Bottcher, C. (2003). The 3D structure of rat DPPIV/CD26 as obtained by cryo-TEM and single particle analysis. Biochemical and Biophysical Research Communications, 304, 73–77.
Ogata, S., Misumi, Y., Tsuji, E., Takami, N., Oda, K., & Ikehara, Y. (1992). Identification of the active site residues in dipeptidyl peptidase IV by affinity labeling and site-directed mutagenesis. Biochemistry, 31, 2582–2587.
Fletcher, S., & Hamilton, A. D. (2006). Targeting protein–protein interactions by rational design: Mimicry of protein surfaces. Journal of the Royal Society, Interface, 3, 215–233.
Chakravarty, S., Yadava, V. S., Kumar, V. K., & Kannan, K. (1985). Drug protein interaction at the molecular level: A study of sulphonamide carbonic anhydrase complexes. Journal of Biosciences, 8, 491–498.
Bienstock, R. J. (2012). Computational drug design targeting protein–protein interactions. Current Pharmaceutical Design, 18, 1240–1254.
Sayers, E. W., Barrett, T., Benson, D. A., Bolton, E., Bryant, S. H., et al. (2011). Database resources of the national center for biotechnology information. Nucleic Acids Research, 39, D38–D51.
Berman, H. M., Westbrook, J., Feng, Z., Gilliland, G., Bhat, T. N., et al. (2000). The protein data bank. Nucleic Acids Research, 28, 235–242.
Laskowski, R. A. (2001). PDBsum, summaries and analyses of PDB structures. Nucleic Acids Research, 29, 221–222.
Laskowski, R. A., Chistyakov, V. V., & Thornton, J. M. (2005). PDBsum more, new summaries and analyses of the known 3D structures of proteins and nucleic acids. Nucleic Acids Research, 33, D266–D268.
Brendel, V., Bucher, P., Nourbakhsh, I., Blaisdell, B. E., & Karlin, S. (1992). Methods and algorithms for statistical analysis of protein sequences. Proceedings of the National Academy of Sciences of the United States of America, 89, 2002–2006.
Cheng, J., Randall, A. Z., Sweredoski, M. J., & Baldi, P. (2005). SCRATCH, a protein structure and structural feature prediction server. Nucleic Acids Research, 33, W72–W76.
Laskowsk, R. A. (2009). PDBsum new things. Nucleic Acids Research, 37, D355–D359.
Hutchinson, E. G., & Thornton, J. M. (1990). HERA, a program to draw schematic diagrams of protein secondary structures. Proteins, 8, 203–212.
Ashkenazy, H., Erez, E., Martz, E., Pupko, T., & Ben-Tal, N. (2010). ConSurf 2010: Calculating evolutionary conservation in sequence and structure of proteins and nucleic acids. Nucleic Acids Research, 38, W529–W533.
Glaser, F., Pupko, T., Paz, I., Bell, R. E., Bechor-Shental, D., et al. (2003). ConSurf: Identification of functional regions in proteins by surface-mapping of phylogenetic information. Bioinformatics, 19, 163–164.
Merritt, E. A., & Bacon, D. J. (1997). Raster3D photorealistic molecular graphics. Methods in Enzymology, 277, 505–524.
Hamby, S. E., & Hirst, J. D. (2008). Prediction of glycosylation sites using random forests. BMC Bioinformatics, 9, 500. doi:10.1186/1471-2105-9-500.
Julenius, K., Mølgaard, A., Gupta, R., & Brunak, S. (2005). Prediction, conservation, analysis, and structural characterization of mammalian mucin-type Oglycosylation sites. Glycobiology, 15, 153–164.
Xue, Y., Liu, Z., Cao, J., Ma, Q., Gao, X., Wang, Q., et al. (2010). GPS 2.1: Enhanced prediction of kinase-specific phosphorylation sites with an algorithm of motif length selection. Protein Engineering, Design & Selection, 24, 255–260.
Wishart, D. S., Knox, C., Guo, A. C., Shrivastava, S., Hassanali, M., Stothard, P., et al. (2006). DrugBank: A comprehensive resource for in silico drug discovery and exploration. Nucleic Acids Research, 34, D668–D672.
Wishart, D. S. (2008). Identifying putative drug targets and potential drug leads: Starting points for virtual screening and docking. Methods in Molecular Biology, 443, 333–351.
Wallace, A. C., Laskowski, R. A., & Thornton, J. M. (1995). LIGPLOT: A program to generate schematic diagrams of protein-ligand interactions. Protein Engineering, 8, 127–134.
Laskowski, R. A., & Swindells, M. B. (2011). LigPlot+: Multiple ligand-protein interaction diagrams for drug discovery. Journal of Chemical Information and Modeling, 51, 2778–2786.
Fleming, P. J., Gong, H., & Rose, G. D. (2006). Secondary structure determines protein topology. Protein Science, 15, 1829–1834.
Taylor, W. R., May, A. C. W., Brown, N. P., & Aszodi, A. (2001). Protein structure: Geometry, topology and classification. Reports on Progress in Physics, 64, 517–590.
Figueiredo, A. M., Moore, G. R., & Whittaker, S. B. (2012). Understanding how small helical proteins fold: Conformational dynamics of Im proteins relevant to their folding landscapes. Biochemical Society Transactions, 40, 424–428.
Moult, J., Fidelis, K., Kryshtafovych, A., Rost, B., & Tramontano, A. (2009). Critical assessment of methods of protein structure prediction: Round VIII. Proteins, 77, 1–4.
Samish, I., MacDermaid, C. M., Perez-Aguilar, J. M., & Saven, J. G. (2011). Theoretical and computational protein design. Annual Review of Physical Chemistry, 62, 129–149.
Magis, C., Gasparini, D., Lecoq, A., Le Du, M. H., Stura, E., et al. (2006). Structure-based secondary structure-independent approach to design protein ligands: Application to the design of Kv1.2 potassium channel blockers. Journal of the American Chemical Society, 128, 16190–16205.
Chakraborty, C., & Agrawal, A. (2013). Computational analysis of C-reactive protein for assessment of molecular dynamics and interaction properties. Cell Biochemistry and Biophysics,. doi:10.1007/s12013-013-9553-4.
Aertgeerts, K., Ye, S., Tennant, M. G., Kraus, M. L., Rogers, J., Sang, B. C., et al. (2004). Crystal structure of human dipeptidyl peptidase IV in complex with a decapeptide reveals details on substrate specificity and tetrahedral intermediate formation. Protein Science, 13, 412–421.
Ma, B., Elkayam, T., Wolfson, H., & Nussinov, R. (2003). Protein-protein interactions, structurally conserved residues distinguish between binding sites and exposed protein surfaces. PNAS USA, 100, 5772–5777.
Shah, Z., Kampfrath, T., Deiuliis, J. A., Zhong, J., Pineda, C., et al. (2011). Long-term dipeptidyl-peptidase 4 inhibition reduces atherosclerosis and inflammation via effects on monocyte recruitment and chemotaxis. Circulation, 124, 2338–2349.
Dong, R. P., Tachibana, K., Hegen, M., Munakata, Y., Cho, D., Schlossman, S. F., et al. (1997). Determination of adenosine deaminase binding domain on CD26 and its immunoregulatory effect on T cell activation. Journal of Immunology, 159, 6070–6076.
Abbott, C. A., McCaughan, G. W., Levy, M. T., Church, W. B., & Gorell, M. D. (1999). Binding to human dipeptidyl peptidase IV by adenosine deaminase and antibodies that inhibit ligand binding involves overlapping, discontinuous sites on a predicted β propeller domain. European Journal of Biochemistry, 266, 798–810.
Takano, K., Yamagata, Y., Funahashi, J., Hioki, Y., Kuramitsu, S., & Yutani, K. (1999). Contribution of intra- and intermolecular hydrogen bonds to the conformational stability of human lysozyme. Biochemistry, 38, 12698–12708.
Royer, W. E, Jr, Strand, K., van Heel, M., & Hendrickson, W. A. (2000). Structural hierarchy in erythrocruorin, the giant respiratory assemblage of annelids. Proceedings of the National Academy of Sciences of the United States of America, 97, 7107–7111.
Knight, J. D., & Miranker, A. D. (2004). Phospholipid catalysis of diabetic amyloid assembly. Journal of Molecular Biology, 341, 1175–1187.
Bourgeas, R., Basse, M. J., Morelli, X., & Roche, P. (2010). Atomic analysis of protein–protein interfaces with known inhibitors, the 2P2I database. PLoS ONE, 5, e9598.
Gromiha, M. M., & Selvaraj, S. (2004). Inter-residue interactions in protein folding and stability. Progress in Biophysics and Molecular Biology, 86, 235–277.
Shakhnovich, E., Abkevich, V., & Ptitsyn, O. (1996). Conserved residues and the mechanism of protein folding. Nature, 379, 96–98.
Teichmann, S. A., Murzin, A. G., & Chothia, C. (2001). Determination of protein function, evolution and interactions by structural genomics. Current Opinion in Structural Biology, 11, 354–363.
Abbott, C. A., McCaughan, G. W., & Gorrell, M. D. (1999). Two highly conserved glutamic acid residues in the predicted β propeller domain of dipeptidyl dipeptidyl peptidase IV are required for its enzyme activity. FEBS Letters, 458, 278–284.
Walsh, C. T., Garneau-Tsodikova, S., & Gatto, J. R. (2005). Protein posttranslational modifications: The chemistry of proteome diversifications. Angewandte Chemie (International ed. in English), 44, 7342–7372.
Aertgeerts, K., Ye, S., Shi, L., Prasad, S. G., Witmer, D., et al. (2004). N-linked glycosylation of dipeptidyl peptidase IV (CD26): Effects on enzyme activity, homodimer formation, and adenosine deaminase binding. Protein Science, 13, 145–154.
Pei, Z. (2007). From the bench to the bedside: Dipeptidyl peptidase IV inhibitors, a new class of oral antihyperglycemic agents. Current Opinion in Drug Discovery & Development, 11, 515–532.
Schweizer, A., Dejager, S., Foley, J. E., Shao, Q., & Kothny, W. (2011). Clinical experience with vildagliptin in the management of type 2 diabetes in a patient population ≥75 years: A pooled analysis from a database of clinical trials. Diabetes, Obesity & Metabolism, 13, 55–64.
Gross, J. L., Rogers, J., Polhamus, D., Gillespie, W., Friedrich, C., Gong, Y., et al. (2013). A novel model-based meta-analysis to indirectly estimate the comparative efficacy of two medications: An example using DPP-4 inhibitors, sitagliptin and linagliptin, in treatment of type 2 diabetes mellitus. BMJ Open, 3, e001844.
Li, J., Klemm, K., O’Farrell, A. M., Guler, H. P., Cherrington, J. M., Schwartz, S., et al. (2010). Evaluation of the potential for pharmacokinetic and pharmacodynamic interactions between dutogliptin, a novel DPP4 inhibitor, and metformin, in type 2 diabetic patients. Current Medical Research and Opinion, 26, 2003–2010.
Engel, M., Hoffmann, T., Wagner, L., Wermann, M., Heiser, U., Kiefersauer, R., et al. (2003). The crystal structure of dipeptidyl peptidase IV (CD26) reveals its functional regulation and enzymatic mechanism. Proceedings of National Academy of Sciences, 100, 5063–5068.
Oefner, C., D’Arcy, A., Mac Sweeney, A., Pierau, S., Gardiner, R., & Dale, G. E. (2003). High-resolution structure of human apo dipeptidyl peptidase IV/CD26 and its complex with 1-[([2-[(5-iodopyridin-2-yl)amino]-ethyl] amino)-acetyl]-2-cyano-(S)-pyrrolidine. Acta Crystallographica Section D: Biological Crystallography, 59, 1206–1212.
Goodarzi, M. O., & Bryer-Ash, M. (2005). Metformin revisited: Reevaluation of its properties and role in the pharmacopoeia of modern antidiabetic agents. Diabetes, Obesity & Metabolism, 7, 654–665.
Gillies, P. S., & Dunn, C. J. (2000). Pioglitazone. Drugs, 60(2), 333–343.
Glandt, M., & Raz, I. (2011). Present and future: Pharmacologic treatment of obesity. Journal of Obesity, 2011, 636181.
Deacon, C. F., Pridal, L., Olesen, M., Klarskov, L., & Holst, J. J. (1996). Dipeptidyl peptidase IV inhibition influences GLP-1 metabolism in vivo (Abstract). Regulatory Peptides, 64, 30.
Janjusevic, R., Quezada, C. M., Small, J., & Stebbins, C. E. (2013). Structure of the HopA1(21-102)-ShcA chaperone-effector complex of Pseudomonas syringae reveals conservation of a virulence factor binding motif from animal to plant pathogens. Journal of Bacteriology, 195(4), 658–664.
Nagpal, I., Raj, I., Subbarao, N., & Gourinath, S. (2012). Virtual screening, identification and in vitro testing of novel inhibitors of O-acetyl-l-serine sulfhydrylase of Entamoeba histolytica. PLoS ONE, 7, e30305.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Chakraborty, C., Hsu, M.J. & Agoramoorthy, G. Understanding the Molecular Dynamics of Type-2 Diabetes Drug Target DPP-4 and its Interaction with Sitagliptin and Inhibitor Diprotin-A. Cell Biochem Biophys 70, 907–922 (2014). https://doi.org/10.1007/s12013-014-9998-0
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12013-014-9998-0