Conformational flexibility of the pharmacologically important insulin analogues
Affiliation(s)
Department of Biochemistry, Saint Petersburg State University, Saint Petersburg, Russia.
Department of Biochemistry, Saint Petersburg State University, Saint Petersburg, Russia.
ABSTRACT
Understanding the conformational flexibility of the insulin drugs is of great importance for the treatment of diabetes mellitus. Once in the body, the drug must have a certain degree of mobility within a specified period of time for the manifestation of its pharmacological properties. This mobility ensures conformational states necessary for binding with the insulin receptor and activating specific biological processes. In this work we investigated conformational flexibility of the pharmacologically important insulin analogues—insulin lispro, insulin aspart, insulin glulisine, and insulin glargine, using the molecular dynamics simulation method. This study provides new insight into the nature of behaviour of A-and B-chains. It has been found out that B-chain substitutions result in rapid acting, while long-lasting action can be achieved by substitutions in both chains. The results of this study can be used for development of new insulin-based antidiabetic drugs.
Understanding the conformational flexibility of the insulin drugs is of great importance for the treatment of diabetes mellitus. Once in the body, the drug must have a certain degree of mobility within a specified period of time for the manifestation of its pharmacological properties. This mobility ensures conformational states necessary for binding with the insulin receptor and activating specific biological processes. In this work we investigated conformational flexibility of the pharmacologically important insulin analogues—insulin lispro, insulin aspart, insulin glulisine, and insulin glargine, using the molecular dynamics simulation method. This study provides new insight into the nature of behaviour of A-and B-chains. It has been found out that B-chain substitutions result in rapid acting, while long-lasting action can be achieved by substitutions in both chains. The results of this study can be used for development of new insulin-based antidiabetic drugs.
Cite this paper
Ksenofontova, O. and Stefanov, V. (2013) Conformational flexibility of the pharmacologically important insulin analogues. Advances in Biological Chemistry, 3, 512-517. doi: 10.4236/abc.2013.35056.
Ksenofontova, O. and Stefanov, V. (2013) Conformational flexibility of the pharmacologically important insulin analogues. Advances in Biological Chemistry, 3, 512-517. doi: 10.4236/abc.2013.35056.
References
[1] Whiting, D.R., Guariguata, L., Weil, C. and 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.
http://dx.doi.org/10.1016/j.diabres.2011.10.029 [2] Eisenbarth, G.S. (1986) Type I diabetes mellitus. A chronic autoimmune disease. The New England Journal of Medicine, 314, 1360-1368.
http://dx.doi.org/10.1056/NEJM198605223142106 [3] Hua, Q., Hu, S., Jia, W., Wang, S. and Weiss, M.A. (2005) Toward the Active Conformation of Insulin. Stereospecific modulation of a structural switch in the B chain. The Journal of Biological Chemistry, 281, 24900-24909.
http://dx.doi.org/10.1074/jbc.M602691200 [4] Olsen, H.B., Ludvigsen, S. and Kaarsholm, N.C. (1996) Solution structure of an engineered insulin monomer at neutral pH. Biochemistry, 35, 8836-8845.
http://dx.doi.org/10.1021/bi960292+ [5] Kurtzhals, P. (2004) Engineering predictability and protraction in a basal insulin analogue: The pharmacology of insulin detemir. International Journal of Obesity, 28, 23-28.
http://dx.doi.org/10.1038/sj.ijo.0802746 [6] Bolli, G.B., Marchi, R.D. Di, Park, G.D., Pramming, S. and Koivisto, V.A. (1999) Insulin analogues and their potential in the management of diabetes mellitus. Diabetologia, 42, 1151-1167.
http://dx.doi.org/10.1007/s001250051286 [7] Hermansen, K., et al. (2004) Insulin analogues (insulin detemir and insulin aspart) versus traditional human insulins (NPH insulin and regular human insulin) in basalbolus therapy for patients with type 1 diabetes. Diabetologia, 47, 622-629.
http://dx.doi.org/10.1007/s00125-004-1365-z [8] Senesh, G., Bushi, D., Neta,A. and O. Yodfat (2010) Compatibility of insulin lispro, aspart, and glulisine with the SoloTMMicroPump, a novel miniature insulin pump. Journal of Diabetes Science and Technology, 4, 104-110. [9] Swinnen, S.G.H.A., et al. (2009) Rationale, design, and baseline data of the insulin glargine (Lantus) versus insulin detemir (Levemir) treat-to-target (L2T3) study: A multinational, randomized noninferiority trial of basal insulin initiation in type 2 diabetes. Diabetes Technology and Therapeutics, 11, 739-743.
http://dx.doi.org/10.1089/dia.2009.0044 [10] Chao, M., et al. (2010) Bioequivalence between two human insulin analogs in chinese population: Glulisine and lispro. Endocrine, 38, 48-52.
http://dx.doi.org/10.1007/s12020-010-9326-4 [11] Setter, S.M., Corbett, C.F., Campbell, R.K. and White, J.R. (2000) Insulin aspart: A new rapid-acting insulin analog. The Annals of Pharmacotherapy, 34, 1423-1431. [12] Garg, S.K., Ellis, S.L. and Ulrich, H. (2005) Insulin glulisine: A new rapid-acting insulin analogue for the treatment of diabetes. Expert Opinion on Pharmacotherapy, 6, 643-651.
http://dx.doi.org/10.1517/14656566.6.4.643 [13] Bolli, G.B. and Owens, D.R. (2000) Insulin glargine. The Lancet, 356, 443-445.
http://dx.doi.org/10.1016/S0140-6736(00)02546-0 [14] Hansen, B.F., et al. (1996) Susteined signalling from the insulin receptor after stimulation with insulin analogues exhibiting increased mitogenic potency. Biochemical Journal, 315, 271-279. [15] Hirsch, I.B. (2005) Drug Therapy Insulin Analogues. The New England Journal of Medicine, 352, 174-183.
http://dx.doi.org/10.1056/NEJMra040832 [16] Karplus, M. and Petsko, G.A. (1990) Molecular dynamics simulations in biology. Nature, 347, 631-639.
http://dx.doi.org/10.1038/347631a0 [17] Karplus, M. and McCammon, A. (2002) Molecular dynamics simulations of biomolecules. Nature Structural Biology, 9, 646-652.
http://dx.doi.org/10.1038/nsb0902-646 [18] Budi, A., Legge, S., Treutlein, H. and Yarovsky, I. (2004) Effect of external stresses on protein conformation: A computer modelling study. European Biophysics Journal, 33, 121-129.
http://dx.doi.org/10.1007/s00249-003-0359-y [19] Legge, F.S., Budi, A., Treutlein, H. and Yarovsky, I. (2006) Protein flexibility: Multiple molecular dynamics simulations of insulin chain B. Biophysical Chemistry, 119, 146-157.
http://dx.doi.org/10.1016/j.bpc.2005.08.002 [20] Zoete, V., Meuwly, M. and Karplus, M. (2005) Study of the insulin dimerization: Binding free energy calculations and per-residue free energy decomposition. Proteins: Structure, Function, and Bioinformatics, 61, 79-93.
http://dx.doi.org/10.1002/prot.20528 [21] Mark, A.E., Berendsen, H.J.C. and Gunsteren, W.F.V. (1991) Conformational flexibility of aqueous monomeric and dimeric insulin: a molecular dynamics study. Biochemistry, 30, 10866-10872.
http://dx.doi.org/10.1021/bi00109a009 [22] Pronk, S., et al. (2013) GROMACS 4.5: A high-throughput and highly parallel open source molecular simulation toolkit. Bioinformatics, 29, 845-854.
http://dx.doi.org/10.1093/bioinformatics/btt055 [23] Eswar, N., Eramian, D., Webb, B., Shen, M. and Sali, A. (2008) Protein structure modeling with MODELLER. Structural Proteomics. Methods in Molecular Biology, 426, 145-159.
http://dx.doi.org/10.1007/978-1-60327-058-8_8 [24] Kaminski, G.A. and Friesner, R.A. (2001) Evaluation and reparametrization of the OPLS-AA force field for proteins via comparison with accurate quantum chemical calculations on peptides. The Journal of Physical Chemistry B, 105, 6474-6487.
http://dx.doi.org/10.1021/jp003919d [25] Humphrey, W., Dalke, A. and Schulten, K. (1996) VMD: Visual molecular dynamics. Journal of Molecular Graphics, 14, 33-38.
http://dx.doi.org/10.1016/0263-7855(96)00018-5 [26] Heller, S., Kozlovski, P. and Kurtzhals, P. (2007) Insulin’s 85th anniversary—An enduring medical miracle. Diabetes Research and Clinical Practice, 78, 149-158.
http://dx.doi.org/10.1016/j.diabres.2007.04.001 [27] Hua, Q. and Weiss, M.A. (2004) Mechanism of insulin fibrillation. The structure of insulin under amyloidogenic conditions resembles a protein-folding. The Journal of Biological Chemistry, 279, 21449-21460.
http://dx.doi.org/10.1074/jbc.M314141200
[1] Whiting, D.R., Guariguata, L., Weil, C. and 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.
http://dx.doi.org/10.1016/j.diabres.2011.10.029 [2] Eisenbarth, G.S. (1986) Type I diabetes mellitus. A chronic autoimmune disease. The New England Journal of Medicine, 314, 1360-1368.
http://dx.doi.org/10.1056/NEJM198605223142106 [3] Hua, Q., Hu, S., Jia, W., Wang, S. and Weiss, M.A. (2005) Toward the Active Conformation of Insulin. Stereospecific modulation of a structural switch in the B chain. The Journal of Biological Chemistry, 281, 24900-24909.
http://dx.doi.org/10.1074/jbc.M602691200 [4] Olsen, H.B., Ludvigsen, S. and Kaarsholm, N.C. (1996) Solution structure of an engineered insulin monomer at neutral pH. Biochemistry, 35, 8836-8845.
http://dx.doi.org/10.1021/bi960292+ [5] Kurtzhals, P. (2004) Engineering predictability and protraction in a basal insulin analogue: The pharmacology of insulin detemir. International Journal of Obesity, 28, 23-28.
http://dx.doi.org/10.1038/sj.ijo.0802746 [6] Bolli, G.B., Marchi, R.D. Di, Park, G.D., Pramming, S. and Koivisto, V.A. (1999) Insulin analogues and their potential in the management of diabetes mellitus. Diabetologia, 42, 1151-1167.
http://dx.doi.org/10.1007/s001250051286 [7] Hermansen, K., et al. (2004) Insulin analogues (insulin detemir and insulin aspart) versus traditional human insulins (NPH insulin and regular human insulin) in basalbolus therapy for patients with type 1 diabetes. Diabetologia, 47, 622-629.
http://dx.doi.org/10.1007/s00125-004-1365-z [8] Senesh, G., Bushi, D., Neta,A. and O. Yodfat (2010) Compatibility of insulin lispro, aspart, and glulisine with the SoloTMMicroPump, a novel miniature insulin pump. Journal of Diabetes Science and Technology, 4, 104-110. [9] Swinnen, S.G.H.A., et al. (2009) Rationale, design, and baseline data of the insulin glargine (Lantus) versus insulin detemir (Levemir) treat-to-target (L2T3) study: A multinational, randomized noninferiority trial of basal insulin initiation in type 2 diabetes. Diabetes Technology and Therapeutics, 11, 739-743.
http://dx.doi.org/10.1089/dia.2009.0044 [10] Chao, M., et al. (2010) Bioequivalence between two human insulin analogs in chinese population: Glulisine and lispro. Endocrine, 38, 48-52.
http://dx.doi.org/10.1007/s12020-010-9326-4 [11] Setter, S.M., Corbett, C.F., Campbell, R.K. and White, J.R. (2000) Insulin aspart: A new rapid-acting insulin analog. The Annals of Pharmacotherapy, 34, 1423-1431. [12] Garg, S.K., Ellis, S.L. and Ulrich, H. (2005) Insulin glulisine: A new rapid-acting insulin analogue for the treatment of diabetes. Expert Opinion on Pharmacotherapy, 6, 643-651.
http://dx.doi.org/10.1517/14656566.6.4.643 [13] Bolli, G.B. and Owens, D.R. (2000) Insulin glargine. The Lancet, 356, 443-445.
http://dx.doi.org/10.1016/S0140-6736(00)02546-0 [14] Hansen, B.F., et al. (1996) Susteined signalling from the insulin receptor after stimulation with insulin analogues exhibiting increased mitogenic potency. Biochemical Journal, 315, 271-279. [15] Hirsch, I.B. (2005) Drug Therapy Insulin Analogues. The New England Journal of Medicine, 352, 174-183.
http://dx.doi.org/10.1056/NEJMra040832 [16] Karplus, M. and Petsko, G.A. (1990) Molecular dynamics simulations in biology. Nature, 347, 631-639.
http://dx.doi.org/10.1038/347631a0 [17] Karplus, M. and McCammon, A. (2002) Molecular dynamics simulations of biomolecules. Nature Structural Biology, 9, 646-652.
http://dx.doi.org/10.1038/nsb0902-646 [18] Budi, A., Legge, S., Treutlein, H. and Yarovsky, I. (2004) Effect of external stresses on protein conformation: A computer modelling study. European Biophysics Journal, 33, 121-129.
http://dx.doi.org/10.1007/s00249-003-0359-y [19] Legge, F.S., Budi, A., Treutlein, H. and Yarovsky, I. (2006) Protein flexibility: Multiple molecular dynamics simulations of insulin chain B. Biophysical Chemistry, 119, 146-157.
http://dx.doi.org/10.1016/j.bpc.2005.08.002 [20] Zoete, V., Meuwly, M. and Karplus, M. (2005) Study of the insulin dimerization: Binding free energy calculations and per-residue free energy decomposition. Proteins: Structure, Function, and Bioinformatics, 61, 79-93.
http://dx.doi.org/10.1002/prot.20528 [21] Mark, A.E., Berendsen, H.J.C. and Gunsteren, W.F.V. (1991) Conformational flexibility of aqueous monomeric and dimeric insulin: a molecular dynamics study. Biochemistry, 30, 10866-10872.
http://dx.doi.org/10.1021/bi00109a009 [22] Pronk, S., et al. (2013) GROMACS 4.5: A high-throughput and highly parallel open source molecular simulation toolkit. Bioinformatics, 29, 845-854.
http://dx.doi.org/10.1093/bioinformatics/btt055 [23] Eswar, N., Eramian, D., Webb, B., Shen, M. and Sali, A. (2008) Protein structure modeling with MODELLER. Structural Proteomics. Methods in Molecular Biology, 426, 145-159.
http://dx.doi.org/10.1007/978-1-60327-058-8_8 [24] Kaminski, G.A. and Friesner, R.A. (2001) Evaluation and reparametrization of the OPLS-AA force field for proteins via comparison with accurate quantum chemical calculations on peptides. The Journal of Physical Chemistry B, 105, 6474-6487.
http://dx.doi.org/10.1021/jp003919d [25] Humphrey, W., Dalke, A. and Schulten, K. (1996) VMD: Visual molecular dynamics. Journal of Molecular Graphics, 14, 33-38.
http://dx.doi.org/10.1016/0263-7855(96)00018-5 [26] Heller, S., Kozlovski, P. and Kurtzhals, P. (2007) Insulin’s 85th anniversary—An enduring medical miracle. Diabetes Research and Clinical Practice, 78, 149-158.
http://dx.doi.org/10.1016/j.diabres.2007.04.001 [27] Hua, Q. and Weiss, M.A. (2004) Mechanism of insulin fibrillation. The structure of insulin under amyloidogenic conditions resembles a protein-folding. The Journal of Biological Chemistry, 279, 21449-21460.
http://dx.doi.org/10.1074/jbc.M314141200