Drug Design of GLP-1 Receptor Agonists: Importance of In Silico Methods

Smriti       Sharma; Vinayak       Bhatia
Abstract

Drug design based on degradation-resistant, long-acting Glucagon-like peptide-1 receptor (GLP-1R) agonists for treating type 2 diabetes is attracting a lot of attention. Here, the authors have examined in detail how in silico drug design is aiding in developing novel GLP-1 receptor agonist drugs. Their pharmacotherapy and adverse effects have also been summarized. After the analysis of currently available information on this topic, the authors feel that in silico method is a great auxiliary tool in almost all the experimental studies on GLP-1 receptors and is highly efficient in identifying novel drug molecules that can act as GLP-1 receptor agonists.
Keywords: GLP-1, Type 2 diabetes mellitus (T2DM), GLP-1 receptor agonists, In Silico, CADDD, molecular docking, drug design.
[1] 
DeFronzo RA, Ferrannini E, Groop L, et al. Type 2 diabetes mellitus. Nat Rev Dis Primers  2015; 1: 15019.
[http://dx.doi.org/10.1038/nrdp.2015.19] [PMID:  27189025] 
[2] 
 Type 2 Diabetes Mellitus, Pandemic In 21st Century.Diabetes
	Advances in Experimental Medicine and Biology. New York, NY:
	Springer 2013; Vol. 771: pp. 42-50. 
[3] 
Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care  2004; 27(5): 1047-53.
[http://dx.doi.org/10.2337/diacare.27.5.1047] [PMID:  15111519] 
[4] 
Zheng Y, Ley SH, Hu FB. Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat Rev Endocrinol  2018; 14(2): 88-98.
[http://dx.doi.org/10.1038/nrendo.2017.151] [PMID:  29219149] 
[5] 
O. L. Olokoba AB,  Obateru OA; Type 2 Diabetes Mellitus: A Review of Current Trends. Oman Med J  2012; 27(4): 269-73.
[6] 
Chen L, Magliano DJ, Zimmet PZ. The worldwide epidemiology of type 2 diabetes mellitus-present and future perspectives. Nat Rev Endocrinol  2011; 8(4): 228-36.
[http://dx.doi.org/10.1038/nrendo.2011.183] [PMID:  22064493] 
[7] 
Boden G, Chen X, Stein TP, Chen X, Stein TP. Gluconeogenesis in moderately and severely hyperglycemic patients with type 2 diabetes mellitus. Am J Physiol Endocrinol Metab  2001; 280(1): E23-30.
[http://dx.doi.org/10.1152/ajpendo.2001.280.1.E23] [PMID:  11120655] 
[8] 
Prattichizzo F, La Sala L, Ceriello A. Two drugs are better than one to start T2DM therapy. Nat Rev Endocrinol  2020; 16(1): 15-6.
[http://dx.doi.org/10.1038/s41574-019-0294-3] [PMID:  31705131] 
[9] 
Farman M, Ghaffar K. The Impact of Diet and Exercise on Diabetic Patients. J Med Biol  2020; 2(1): 25-30.
[10] 
England CY, Andrews RC. James Lind Alliance research priorities: should diet and exercise be used as an alternative to drugs for the management of type 2 diabetes or alongside them? Diabet Med  2020; 37(4): 564-72.
[http://dx.doi.org/10.1111/dme.14217] [PMID:  31849092] 
[11] 
Chaudhury A, Duvoor C, Reddy Dendi VS, et al. Clinical Review of Antidiabetic Drugs: Implications for Type 2 Diabetes Mellitus Management. Front Endocrinol (Lausanne)  2017; 8(January): 6.
[http://dx.doi.org/10.3389/fendo.2017.00006] [PMID:  28167928] 
[12] 
Magkos F, Yannakoulia M, Chan JL, Mantzoros CS. Management of the metabolic syndrome and type 2 diabetes through lifestyle modification. Annu Rev Nutr  2009; 29: 223-56.
[http://dx.doi.org/10.1146/annurev-nutr-080508-141200] [PMID:  19400751] 
[13] 
Bailey CJ, Tahrani AA, Barnett AH. Future glucose-lowering drugs for type 2 diabetes. Lancet Diabetes Endocrinol  2016; 4(4): 350-9.
[http://dx.doi.org/10.1016/S2213-8587(15)00462-3] [PMID:  26809680] 
[14] 
Soccio RE, Chen ER, Lazar MA. Thiazolidinediones and the promise of insulin sensitization in type 2 diabetes. Cell Metab  2014; 20(4): 573-91.
[http://dx.doi.org/10.1016/j.cmet.2014.08.005] [PMID:  25242225] 
[15] 
Satirapoj B, Pratipanawatr T, Ongphiphadhanakul B, Suwanwalaikorn S, Benjasuratwong Y, Nitiyanant W. world Evaluation of glycemic control and hypoglycemic Events among type 2 Diabetes mellitus study (REEDS): sectional study a multicentre, cross- in Thailand. BMJ Open  2020; 10: 1-11.
[http://dx.doi.org/10.1136/bmjopen-2019-031612] [PMID:  32051301] 
[16] 
Giorgino F, Laviola L, Leonardini A, Natalicchio A. GLP-1: a new approach for type 2 diabetes therapy. Diab Res Clin Pract  2006; 74: 152-5.
[17] 
Liang YL, Belousoff MJ, Zhao P, et al. Toward a Structural Understanding of Class B GPCR Peptide Binding and Activation. Mol Cell  2020; 77(3): 656-668.e5.
[http://dx.doi.org/10.1016/j.molcel.2020.01.012] [PMID:  32004469] 
[18] 
Rosenbaum DM, Rasmussen SGF, Kobilka BK. The structure and function of G-protein-coupled receptors. Nature  2009; 459(7245): 356-63.
[http://dx.doi.org/10.1038/nature08144] [PMID:  19458711] 
[19] 
Girdhar K, Dehury B, Kumar Singh M, et al. Novel insights into the dynamics behavior of glucagon-like peptide-1 receptor with its small molecule agonists. J Biomol Struct Dyn  2019; 37(15): 3976-86.
[http://dx.doi.org/10.1080/07391102.2018.1532818] [PMID:  30296922] 
[20] 
N (US)) Mohan Rao (Greensboro) Ligands for the GLP-1 receptor
	and methods for discovery thereof United States Pat US
	8718994, 
[21] 
Uccellatore A, Genovese S, Dicembrini I, Mannucci E, Ceriello A. Comparison Review of Short-Acting and Long-Acting Glucagon-like Peptide-1 Receptor Agonists. Diabetes Ther  2015; 6(3): 239-56.
[http://dx.doi.org/10.1007/s13300-015-0127-x] [PMID:  26271795] 
[22] 
Trujillo J M, Nuffer W, Ellis S L. GLP-1 receptor agonists: a review of head- to-head clinical studies 2015; 19-2 
[http://dx.doi.org/10.1177/2042018814559725] 
[23] 
Prasad-reddy L, Isaacs D. REVIEW A clinical review of GLP-1 receptor agonists : efficacy and safety in diabetes and beyond Incretin hormones and diabetes GLP-1 and GIP Pharmacologic profiles, safety, and efficacy of approved agents Exenatide pharmacology 2015. 1-19.. 
[24] 
Zhang Y, Sun B, Feng D, et al. Cryo-EM structure of the activated GLP-1 receptor in complex with a G protein. Nature  2017; 546(7657): 248-53.
[http://dx.doi.org/10.1038/nature22394] [PMID:  28538729] 
[25] 
Sharma S, Bhatia V. Treatment of Type 2 Diabetes mellitus (T2DM): Can GLP-1 Receptor Agonists fill in the gaps? Chem Biol Lett  2020; 7(4): 215-24.
[26] 
Davies MJ, D’Alessio DA, Fradkin J, et al. Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care  2018; 41(12): 2669-701.
[http://dx.doi.org/10.2337/dci18-0033] [PMID:  30291106] 
[27] 
Vilsbøll T, Holst JJ. Incretins, insulin secretion and Type 2 diabetes mellitus. Diabetologia  2004; 47(3): 357-66.
[http://dx.doi.org/10.1007/s00125-004-1342-6] [PMID:  14968296] 
[28] 
Holst JJ. Incretin therapy for diabetes mellitus type 2. Curr Opin Endocrinol Diabetes Obes Febr  2020; 27(1): 2-10.
[http://dx.doi.org/10.1097/MED.0000000000000516] 
[29] 
Nauck MA. The rollercoaster history of using physiological and pharmacological properties of incretin hormones to develop diabetes medications with a convincing benefit-risk relationship. Metabolism  2020; 103154031
[http://dx.doi.org/10.1016/j.metabol.2019.154031] [PMID:  31785258] 
[30] 
Stensen S, Rosenkilde MM. Evaluation of the incretin effect in humans using GIP and GLP-1 receptor antagonists. Peptides  2020; 170-83.
[31] 
Christensen MB, Gasbjerg LS, Heimbürger SM, Stensen S, Vilsbøll T, Knop FK. GIP’s involvement in the pathophysiology of type 2 diabetes. Peptides  2020; 125(March)170178
[http://dx.doi.org/10.1016/j.peptides.2019.170178] [PMID:  31682875] 
[32] 
Samms RJ, Coghlan MP, Sloop KW. How May GIP Enhance the Therapeutic Efficacy of GLP-1? Trends Endocrinol Metab  2020; 31(6): 410-21.
[http://dx.doi.org/10.1016/j.tem.2020.02.006] [PMID:  32396843] 
[33] 
Fava GE, Dong EW, Wu H. Intra-islet glucagon-like peptide 1. J Diabetes Complications  2016; 30(8): 1651-8.
[http://dx.doi.org/10.1016/j.jdiacomp.2016.05.016] [PMID:  27267264] 
[34] 
Edwards CMB, Todd JF, Mahmoudi M, et al. Glucagon-like peptide 1 has a physiological role in the control of postprandial glucose in humans: studies with the antagonist exendin 9-39. Diabetes  1999; 48(1): 86-93.
[http://dx.doi.org/10.2337/diabetes.48.1.86] [PMID:  9892226] 
[35] 
Bharatam PV, Patel DS, Adane L, Mittal A, Sundriyal S. Modeling and informatics in designing anti-diabetic agents. Curr Pharm Des  2007; 13(34): 3518-30.
[http://dx.doi.org/10.2174/138161207782794239] [PMID:  18220788] 
[36] 
Morgan L. Challenges and opportunities in managing type 2 diabetes. Am Health Drug Benefits  2017; 10(4): 197-200.
[PMID: 28794823] 
[37] 
Tjokroprawiro A. New approach in the treatment of T2DM and metabolic syndrome (focus on a novel insulin sensitizer). Acta Med Indones  2006; 38(3): 160-6.
[PMID: 17119268] 
[38] 
Zhao Q, Yu H, Ji M, Zhao Y, Chen X. Computational Model Development of Drug-Target Interaction Prediction: A Review. Curr Protein Pept Sci  2019; 492-4.
[http://dx.doi.org/10.2174/1389203720666190123164310] 
[39] 
Bell RO, Roblin PH, et al. The Many Roles of Computation in Drug Discovery. Drug Discov Today  2014; 5(1): 1-19.
[http://dx.doi.org/10.1039/d0cs00098a] 
[40] 
Kumar V, Dhanjal JK, Bhargava P, et al. Withanone and Withaferin-A are predicted to interact with transmembrane protease serine 2 (TMPRSS2) and block entry of SARS-CoV-2 into cells. J Biomol Struct Dyn  2020; 1-13.
[http://dx.doi.org/10.1080/07391102.2020.1775704] [PMID:  32469279] 
[41] 
Dangi M, Khichi A. Relevance of Molecular Docking Studies in Drug Designing. Curr Bioinform  2020; 15(4): 2020.
[42] 
Sharma S, Bhatia V. Phytochemicals for drug discovery in Alzheimer’s disease: In silico Advances. Curr Pharm Des  2020; 27: 1-13.
[http://dx.doi.org/10.2174/1381612826666200928161721] [PMID:  32988343] 
[43] 
Waterhouse A, Bertoni M, Bienert S, et al. SWISS-MODEL: homology modelling of protein structures and complexes. Nucleic Acids Res  2018; 46(W1)W296-303
[http://dx.doi.org/10.1093/nar/gky427] [PMID:  29788355] 
[44] 
Brogi S, Ramalho TC, Kuca K, Medina-Franco JL, Valko M. Editorial: In silico Methods for Drug Design and Discovery. Front Chem  2020; 8(August): 612.
[http://dx.doi.org/10.3389/fchem.2020.00612] [PMID:  32850641] 
[45] 
Sharma S, Bhatia V. Nanoscale Drug Delivery Systems for Glaucoma: Experimental and In Silico Advances. Curr Top Med Chem 2020.
[http://dx.doi.org/10.2174/1568026620666200922114210] [PMID:  32962618] 
[46] 
Mapari S, Camarda KV. Use of three-dimensional descriptors in molecular design for biologically active compounds. Curr Opin Chem Eng  2019; 27: 60-4.
[http://dx.doi.org/10.1016/j.coche.2019.11.011] 
[47] 
Duarte Y, Márquez-Miranda V, Miossec MJ, González-Nilo F. Integration of target discovery, drug discovery and drug delivery: A review on computational strategies. Wiley Interdiscip Rev Nanomed Nanobiotechnol  2019; 11(4)e1554
[http://dx.doi.org/10.1002/wnan.1554] [PMID:  30932351] 
[48] 
Chaudhary KK, Mishra N. A Review on Molecular Docking. Novel Tool Drug Discov  2016; 4: 1-4.
[49] 
Paquet E, Viktor HL, Simulations MC. Molecular dynamics, monte carlo simulations, and langevin dynamics: a computational review. BioMed Res Int  2015; 2015183918
[http://dx.doi.org/10.1155/2015/183918] [PMID:  25785262] 
[50] 
Sharma S, Bhatia V. Appraisal of the role of In silico Methods in Pyrazole based drug design. Mini Rev Med Chem  2021; 21(2): 204-16.
[51] 
Scior T. QSAR without borders. Drug Discov Today  2014; 5(1): 1-4.
[http://dx.doi.org/10.1126/science.1096361] 
[52] 
Amin SA, Ghosh K, Gayen S, Jha T. Chemical-informatics approach to COVID-19 drug discovery: Monte Carlo based QSAR, virtual screening and molecular docking study of some in-house molecules as papain-like protease (PLpro) inhibitors. J Biomol Struct Dyn  2020; 1-10.
[http://dx.doi.org/10.1080/07391102.2020.1780946] [PMID:  32568618] 
[53] 
Kumar Y, Singh H, Patel CN. In silico prediction of potential inhibitors for the main protease of SARS-CoV-2 using molecular docking and dynamics simulation based drug-repurposing. J Infect Public Health  2020; 13(9): 1210-23.
[http://dx.doi.org/10.1016/j.jiph.2020.06.016] [PMID:  32561274] 
[54] 
Keating GM. Exenatide. Drugs  2005; 65(12): 1681-92.
[http://dx.doi.org/10.2165/00003495-200565120-00008] [PMID:  16060703] 
[55] 
Nielsen L L, Young A A, Parkes D G. Pharmacology of exenatide
	(synthetic exendin-4): a potential therapeutic for improved glycemic
	control of type 2 diabetes. 2004; 117: 77-88.. 
[http://dx.doi.org/10.1016/j.regpep.2003.10.028] 
[56] 
Bray GM. Exenatide. Am J Health Syst Pharm  2006; 63(5): 411-8.
[http://dx.doi.org/10.2146/ajhp050459] [PMID:  16484515] 
[57] 
Johansen NJ, Dejgaard TF, Lund A, et al. Efficacy and safety of meal-time administration of short-acting exenatide for glycaemic control in type 1 diabetes (MAG1C): a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol  2020; 8(4): 313-24.
[http://dx.doi.org/10.1016/S2213-8587(20)30030-9] [PMID:  32135138] 
[58] 
Cai Y. Long-acting preparations of exenatide. Drug Des Devel Ther  2013; 7: 963-70.
[59] 
Mehta A, Marso SP, Neeland IJ. Liraglutide for weight management: a critical review of the evidence. Obes Sci Pract  2017; 3(1): 3-14.
[http://dx.doi.org/10.1002/osp4.84] [PMID:  28392927] 
[60] 
Neumiller JJ. Differential chemistry (structure), mechanism of
	action, and pharmacology of GLP-1 receptor agonists and DPP-4 inhibitors
	J Am Pharm Assoc (2003) 2009; 49(5)(Suppl 1): S16-29 
[http://dx.doi.org/10.1331/JAPhA.2009.09078] [PMID: 19801361] 
[61] 
Rosenstock J, Reusch J, Bush M, Yang F, Stewart M. Albiglutide Study Group. Potential of albiglutide, a long-acting GLP-1 receptor agonist, in type 2 diabetes: a randomized controlled trial exploring weekly, biweekly, and monthly dosing. Diabetes Care  2009; 32(10): 1880-6.
[http://dx.doi.org/10.2337/dc09-0366] [PMID:  19592625] 
[62] 
Umpierrez G, Tofé Povedano S, Pérez Manghi F, Shurzinske L, Pechtner V. Efficacy and safety of dulaglutide monotherapy versus metformin in type 2 diabetes in a randomized controlled trial (AWARD-3). Diabetes Care  2014; 37(8): 2168-76.
[http://dx.doi.org/10.2337/dc13-2759] [PMID:  24842985] 
[63] 
Henry RR, Logan D, Alessi T, Baron MA. A randomized, open-label, multicenter, 4-week study to evaluate the tolerability and pharmacokinetics of ITCA 650 in patients with type 2 diabetes. Clin Ther  2013; 35(5): 634-645.e1.
[http://dx.doi.org/10.1016/j.clinthera.2013.03.011] [PMID:  23578605] 
[64] 
R. Azeem , P.Prabhakar , L.Kjems , H.Huang , and M.A.Baron . Efficacy and Safety of ITCA 650, a Novel Drug-Device GLP-1 Receptor Agonist, in Type 2 Diabetes Uncontrolled With Oral Antidiabetes Drugs: The FREEDOM-1 Trial. Diabetes Care  2017; 41(2): 33-340.
[http://dx.doi.org/10.2337/dc17-1306/-/DC1] 
[65] 
Kalra S, Das AK, Sahay RK, et al. Consensus Recommendations on GLP-1 RA Use in the Management of Type 2 Diabetes Mellitus: South Asian Task Force. Diabetes Ther  2019; 10(5): 1645-717.
[http://dx.doi.org/10.1007/s13300-019-0669-4] [PMID:  31359367] 
[66] 
Gerstein HC, Colhoun HM, Dagenais GR, et al. REWIND Investigators. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet  2019; 394(10193): 121-30.
[http://dx.doi.org/10.1016/S0140-6736(19)31149-3] [PMID:  31189511] 
[67] 
Hinnen D. Glucagon-Like Peptide 1 Receptor Agonists for Type 2 Diabetes. Diabetes Spectr  2017; 30(3): 202-10.
[http://dx.doi.org/10.2337/ds16-0026] 
[68] 
Dungan K, Eliaschewitz FG, Thomsen M, Sc DM, Vilsbøll T, Sc DM. “Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes,” new engl J. Med Orig  2019; 381: 841-51.
[http://dx.doi.org/10.1056/NEJMoa1901118] 
[69] 
Carracher, Payal H. Marathe, and Kelly L. Close are of Close Concerns a healthcare information company focused exclusively on diabetes and obesity care. Close Concerns publishes. J Diabetes 2018; 10(7): 541-5 http://www.closeconcerns.com
[70] 
Hare KJ, Vilsbøll T, Asmar M, Deacon CF, Knop FK, Holst JJ. The Glucagonostatic and Insulinotropic Effects of Glucose-Lowering Action. Diabetes  2010; 59: 1765-70.
[http://dx.doi.org/10.2337/db09-1414] [PMID:  20150286] 
[71] 
Doyle ME, Egan JM. Mechanisms of action of glucagon-like peptide 1 in the pancreas. Pharmacol Ther  2007; 113(3): 546-93.
[http://dx.doi.org/10.1016/j.pharmthera.2006.11.007] [PMID:  17306374] 
[72] 
Meier JJ, Gethmann A, Götze O, et al. Glucagon-like peptide 1 abolishes the postprandial rise in triglyceride concentrations and lowers levels of non-esterified fatty acids in humans. Diabetologia  2006; 49(3): 452-8.
[http://dx.doi.org/10.1007/s00125-005-0126-y] [PMID:  16447057] 
[73] 
Mathieu C, Bollaerts K. Antihyperglycaemic therapy in elderly patients with type 2 diabetes: potential role of incretin mimetics and DPP-4 inhibitors. Int J Clin Pract Suppl  2007; 61(154): 29-37.
[http://dx.doi.org/10.1111/j.1742-1241.2007.01437.x] [PMID:  17593275] 
[74] 
Lapolla A, Genovese S, Giorgino F, et al. Patient-reported outcomes in elderly patients with type 2 diabetes mellitus treated with dual oral therapy: a multicenter, observational study from Italy. Curr Med Res Opin  2020; 36(4): 555-62.
[http://dx.doi.org/10.1080/03007995.2019.1707649] [PMID:  31868033] 
[75] 
Aroda VR. A review of GLP-1 receptor agonists : Evolution and advancement, through the lens of randomised controlled trials. Diabetes Obes Metab  2018; 20: 22-33.
[http://dx.doi.org/10.1111/dom.13162] 
[76] 
P.- Receptor, A. Da Costa, D. Drucker, and B. Thorens; Glucose Competence of the Hepatoportal Vein Sensor Requires the Presence of an Activated Glucagon-Like peptide-1 receptor. Diabetes  2001; 50(8): 1720-8.
[77] 
Lingohr MK, Buettner R, Rhodes CJ. Pancreatic β-cell growth and survival-a role in obesity-linked type 2 diabetes? Trends Mol Med  2002; 8(8): 375-84.
[http://dx.doi.org/10.1016/S1471-4914(02)02377-8] [PMID:  12127723] 
[78] 
Chon S, Gautier J. An Update on the Effect of Incretin-Based Therapies on β-Cell Function and Mass. Diabetes Metab J  2016; 40(2): 99-114.
[79] 
Falkner B, Cossrow ND, Cossrow H. Prevalence of metabolic syndrome and obesity-associated hypertension in the racial ethnic minorities of the United States. Curr Hypertens Rep  2014; 16(7): 449-56.
[http://dx.doi.org/10.1007/s11906-014-0449-5] [PMID:  24819559] 
[80] 
Dar S. The role of GLP-1 receptor agonists as weight loss agents in patients with and without type 2 diabetes  2015; 32(8)
[http://dx.doi.org/10.1002/pdi.1978] 
[81] 
Lamos EM, Malek R, Davis SN, Mary E, Malek R, Glp SND. GLP-1 receptor agonists in the treatment of polycystic ovary syndrome. Expert Rev Clin Pharmacol  2017; 10(4): 401-8.
[http://dx.doi.org/10.1080/17512433.2017.1292125] [PMID:  28276778] 
[82] 
Sirmans SM, Pate KA. Epidemiology, diagnosis, and management of polycystic ovary syndrome. Clin Epidemiol  2013; 6: 1-13.
[http://dx.doi.org/10.2147/CLEP.S37559] [PMID:  24379699] 
[83] 
 C. N. S. P. S. S. Domenico, T. G. C. G. L. S. Annamaria, and C. B. O. Yildiz Obesity, type 2 diabetes mellitus and cardiovascular disease risk:an uptodate in the management of Polycystic Ovary Syndrome. Eur J Obstet Gynecol  2016; 207: 213-9.
[http://dx.doi.org/10.1016/j.ejogrb.2016.08.026] 
[84] 
Frías J P. Exenatide once weekly plus dapagliflozin once daily
	versus exenatide or dapagliflozin alone in patients with type 2 diabetes
inadequately controlled with metformin double-blind , phase
	3 , randomised controlled trial. 2016; 4(12): 1004-16.. 
[http://dx.doi.org/10.1016/S2213-8587(16)30267-4] 
[85] 
Sun F, Wu S, Guo S, et al. Impact of GLP-1 receptor agonists on blood pressure, heart rate and hypertension among patients with type 2 diabetes: A systematic review and network meta-analysis. Diabetes Res Clin Pract  2015; 110(1): 26-37.
[http://dx.doi.org/10.1016/j.diabres.2015.07.015] [PMID:  26358202] 
[86] 
Rowlands J, Heng J, Newsholme P, Carlessi R. Pleiotropic Effects of GLP-1 and Analogs on Cell Signaling, Metabolism, and Function. Front Endocrinol (Lausanne)  2018; 9(672): 672.
[http://dx.doi.org/10.3389/fendo.2018.00672] [PMID:  30532733] 
[87] 
Sokos GG, Nikolaidis LA, Mankad S, Elahi D, Shannon RP. Glucagon-like peptide-1 infusion improves left ventricular ejection fraction and functional status in patients with chronic heart failure. J Card Fail  2006; 12(9): 694-9.
[http://dx.doi.org/10.1016/j.cardfail.2006.08.211] [PMID:  17174230] 
[88] 
Clarke SJ. GLP - 1 Is a Coronary Artery Vasodilator in Humans J Am Heart Assoc 2018; 7(22): 4: 1-14 
[http://dx.doi.org/10.1161/JAHA.118.010321] 
[89] 
von Scholten BJ, Hansen TW, Goetze JP, Persson F, Rossing P. Glucagon-like peptide 1 receptor agonist (GLP-1 RA): long-term effect on kidney function in patients with type 2 diabetes. J Diabetes Complications  2015; 29(5): 670-4.
[http://dx.doi.org/10.1016/j.jdiacomp.2015.04.004] [PMID:  25935863] 
[90] 
Jardine MJ, Hata J, Woodward M, et al.  ADVANCE Collaborative Group. Prediction of kidney-related outcomes in patients with type 2 diabetes. Am J Kidney Dis  2012; 60(5): 770-8.
[http://dx.doi.org/10.1053/j.ajkd.2012.04.025] [PMID:  22694950] 
[91] 
Thomas MC. The potential and pitfalls of GLP-1 receptor agonists
	for renal protection in type 2 diabetes. Diabetes Metab 2017;
	43(Suppl. 1): 2S20-2S27.. 
[http://dx.doi.org/10.1016/S1262-3636(17)30069-1] 
[92] 
Cuthbertson DJ, et al. Improved Glycaemia Correlates with Liver Fat Reduction in Obese, Type 2 Diabetes, Patients Given Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists. PLoS One  2012; 7(12): 8-11.
[http://dx.doi.org/10.1371/journal.pone.0050117] 
[93] 
Meier JJ. REVIEWS treatment of type 2 diabetes mellitus. Nat Publ Gr  2012; 1: 1-15.
[http://dx.doi.org/10.1038/nrendo.2012.140] [PMID:  22945360] 
[94] 
Marathe CS, Rayner CK, Jones KL, Horowitz M. Effects of GLP-1 and incretin-based therapies on gastrointestinal motor function. Exp Diabetes Res  2011; 2011279530
[http://dx.doi.org/10.1155/2011/279530] [PMID:  21747825] 
[95] 
Filippatos TD, Panagiotopoulou TV, Elisaf MS, Elisaf MS. Adverse Effects of GLP-1 Receptor Agonists. Rev Diabet Stud  2014; 11(3-4): 202-30.
[http://dx.doi.org/10.1900/RDS.2014.11.202] [PMID:  26177483] 
[96] 
Jacobson KA. New paradigms in GPCR drug discovery. Biochem Pharmacol  2015; 98(4): 541-55.
[http://dx.doi.org/10.1016/j.bcp.2015.08.085] [PMID:  26265138] 
[97] 
Kooistra AJ, Roumen L, Leurs R, De Esch IJP. From Heptahelical Bundle to Hits from the Haystack : Structure-Based Virtual Screening for GPCR Ligands.  1st ed. Elsevier Inc. 2013; Vol. 522.
[http://dx.doi.org/10.1016/B978-0-12-407865-9.00015-7] 
[98] 
Qu X, Wang D, Wu B. Progress in GPCR structure determination. Elsevier Inc. 2020.
[http://dx.doi.org/10.1016/B978-0-12-816228-6.00001-5] 
[99] 
Tan B, Liu M. Newly characterized crystal structures: further insights into the architecture of GPCRs. Sci China Life Sci  2018; 61(5): 593-6.
[http://dx.doi.org/10.1007/s11427-017-9159-6] [PMID:  29285710] 
[100] 
Siu FY, He M, de Graaf C, et al. Structure of the human glucagon class B G-protein-coupled receptor. Nature  2013; 499(7459): 444-9.
[http://dx.doi.org/10.1038/nature12393] [PMID:  23863937] 
[101] 
Bergwitz C, Gardella TJ, Flannery MR, et al. Full activation of chimeric receptors by hybrids between parathyroid hormone and calcitonin. Evidence for a common pattern of ligand-receptor interaction. J Biol Chem  1996; 271(43): 26469-72.
[http://dx.doi.org/10.1074/jbc.271.43.26469] [PMID:  8900113] 
[102] 
Runge S, Wulff BS, Madsen K, Bräuner-Osborne H, Knudsen LB. Different domains of the glucagon and glucagon-like peptide-1 receptors provide the critical determinants of ligand selectivity. Br J Pharmacol  2003; 138(5): 787-94.
[http://dx.doi.org/10.1038/sj.bjp.0705120] [PMID:  12642379] 
[103] 
Al-Sabah S, Donnelly D. A model for receptor-peptide binding at the glucagon-like peptide-1 (GLP-1) receptor through the analysis of truncated ligands and receptors. Br J Pharmacol  2003; 140(2): 339-46.
[http://dx.doi.org/10.1038/sj.bjp.0705453] [PMID:  12970080] 
[104] 
Mann R, Nasr N, Hadden D, et al. Peptide binding at the GLP-1 receptor. Biochem Soc Trans  2007; 35(Pt 4): 713-6.
[http://dx.doi.org/10.1042/BST0350713] [PMID:  17635131] 
[105] 
Audie J, Boyd C. The synergistic use of computation, chemistry and biology to discover novel peptide-based drugs: the time is right. Curr Pharm Des  2010; 16(5): 567-82.
[http://dx.doi.org/10.2174/138161210790361425] [PMID:  19929848] 
[106] 
Redij T, Ma J, Li Z, Hua X, Li Z. Discovery of a potential positive allosteric modulator of glucagon-like peptide 1 receptor through virtual screening and experimental study. J Comput Aided Mol Des  2019; 33(11): 973-81.
[http://dx.doi.org/10.1007/s10822-019-00254-4] [PMID:  31758355] 
[107] 
Pissarnitski DA, Zhao Z, Cole D, et al. Scaffold-hopping from xanthines to tricyclic guanines: A case study of dipeptidyl peptidase 4 (DPP4) inhibitors. Bioorg Med Chem  2016; 24(21): 5534-45.
[http://dx.doi.org/10.1016/j.bmc.2016.09.007] [PMID:  27670099] 
[108] 
Han J, Huang X, Sun L, Li Z, Qian H, Huang W. Novel fatty chain-modified glucagon-like peptide-1 conjugates with enhanced stability and prolonged in vivo activity. Biochem Pharmacol  2013; 86(2): 297-308.
[http://dx.doi.org/10.1016/j.bcp.2013.05.012] [PMID:  23707756] 
[109] 
Deng X. Drug discovery approaches targeting the incretin pathway. Bioorg Chem  2020.In press
[110] 
Jazayeri A, Rappas M, Brown AJH, et al. Crystal structure of the GLP-1 receptor bound to a peptide agonist. Nature  2017; 546(7657): 254-8.
[http://dx.doi.org/10.1038/nature22800] [PMID:  28562585] 
[111] 
López de Maturana R, Treece-Birch J, Abidi F, Findlay JB, Donnelly D. Met-204 and Tyr-205 are together important for binding GLP-1 receptor agonists but not their N-terminally truncated analogues. Protein Pept Lett  2004; 11(1): 15-22.
[http://dx.doi.org/10.2174/0929866043478491] [PMID:  14965274] 
[112] 
Hoare SRJ. Mechanisms of peptide and nonpeptide ligand binding to Class B G-protein-coupled receptors. Drug Discov Today  2005; 10(6): 417-27.
[http://dx.doi.org/10.1016/S1359-6446(05)03370-2] [PMID:  15808821] 
[113] 
Lin F, Wang R. Molecular modeling of the three-dimensional structure of GLP-1R and its interactions with several agonists. J Mol Model  2009; 15(1): 53-65.
[http://dx.doi.org/10.1007/s00894-008-0372-2] [PMID:  18941807] 
[114] 
Chen D, Liao J, Li N, et al. A nonpeptidic agonist of glucagon-like peptide 1 receptors with efficacy in diabetic db/db mice. Proc Natl Acad Sci USA  2007; 104(3): 943-8.
[http://dx.doi.org/10.1073/pnas.0610173104] [PMID:  17213311] 
[115] 
Knudsen LB, Kiel D, Teng M, et al. Small-molecule agonists for the glucagon-like peptide 1 receptor. Proc Natl Acad Sci USA  2007; 104(3): 937-42.
[http://dx.doi.org/10.1073/pnas.0605701104] [PMID:  17213325] 
[116] 
Gallwitz B, Witt M, Paetzold G, Morys-wortmann C, Zimmermann B. Structure / activity characterization of glucagon-like peptide- 1 1994; 1156: 1151-6.. 
[http://dx.doi.org/10.1111/j.1432-1033.1994.1151b.x] 
[117] 
Xiao Q, Jeng W, Wheeler MB. Characterization of glucagon-like peptide-1 receptor-binding determinants. J Mol Endocrinol  2000; 25(3): 321-35.
[http://dx.doi.org/10.1677/jme.0.0250321] [PMID:  11116211] 
[118] 
Al-Sabah S, Donnelly D. The positive charge at Lys-288 of the glucagon-like peptide-1 (GLP-1) receptor is important for binding the N-terminus of peptide agonists. FEBS Lett  2003; 553(3): 342-6.
[http://dx.doi.org/10.1016/S0014-5793(03)01043-3] [PMID:  14572647] 
[119] 
López de Maturana R, Donnelly D. The glucagon-like peptide-1 receptor binding site for the N-terminus of GLP-1 requires polarity at Asp198 rather than negative charge. FEBS Lett  2002; 530(1-3): 244-8.
[http://dx.doi.org/10.1016/S0014-5793(02)03492-0] [PMID:  12387900] 
[120] 
Adelhorst K, Hedegaard BB, Knudsen LB, Kirk O. Structure-activity studies of glucagon-like peptide-1. J Biol Chem  1994; 269(9): 6275-8.
[PMID: 8119974] 
[121] 
Pan CQ, Buxton JM, Yung SL, et al. Design of a long acting peptide functioning as both a glucagon-like peptide-1 receptor agonist and a glucagon receptor antagonist. J Biol Chem  2006; 281(18): 12506-15.
[http://dx.doi.org/10.1074/jbc.M600127200] [PMID:  16505481] 
[122] 
Thornberry NA, Gallwitz B. Best Practice & Research Clinical Endocrinology & Metabolism Mechanism of action of inhibitors of dipeptidyl-peptidase-4. Best Pract Res Clin Endocrinol Metab  2009; 23(4): 479-86.
[http://dx.doi.org/10.1016/j.beem.2009.03.004] [PMID:  19748065] 
[123] 
Wilmen A, Van Eyll B, Göke B, Göke R. Five out of six tryptophan residues in the N-terminal extracellular domain of the rat GLP-1 receptor are essential for its ability to bind GLP-1. Peptides  1997; 18(2): 301-5.
[http://dx.doi.org/10.1016/S0196-9781(96)00321-X] [PMID:  9149304] 
[124] 
Redij T, Chaudhari R, Li Z, Hua X, Li Z. Structural Modeling and in Silico Screening of Potential Small-Molecule Allosteric Agonists of a Glucagon-like Peptide 1 Receptor. ACS Omega  2019; 4(1): 961-70.
[http://dx.doi.org/10.1021/acsomega.8b03052] [PMID:  31459371] 
[125] 
Khoury E, Clément S, Laporte SA. Allosteric and biased g protein-coupled receptor signaling regulation: potentials for new therapeutics. Front Endocrinol (Lausanne)  2014; 5(68): 68.
[http://dx.doi.org/10.3389/fendo.2014.00068] [PMID:  24847311] 
[126] 
Wootten D, Miller LJ, Koole C, Christopoulos A, Sexton PM. Allostery and Biased Agonism at Class B G Protein-Coupled Receptors. Chem Rev  2017; 117(1): 111-38.
[http://dx.doi.org/10.1021/acs.chemrev.6b00049] [PMID:  27040440] 
[127] 
Pupo AS, Duarte DA, Lima V, Teixeira LB. Parreiras-E-Silva LT, Costa-Neto CM. Recent updates on GPCR biased agonism. Pharmacol Res  2016; 112: 49-57.
[http://dx.doi.org/10.1016/j.phrs.2016.01.031] [PMID:  26836887] 
[128] 
Song G, Yang D, Wang Y, et al. Human GLP-1 receptor transmembrane domain structure in complex with allosteric modulators. Nature  2017; 546(7657): 312-5.
[http://dx.doi.org/10.1038/nature22378] [PMID:  28514449] 
[129] 
Liang YL, Khoshouei M, Glukhova A, et al. Phase-plate cryo-EM structure of a biased agonist-bound human GLP-1 receptor-Gs complex. Nature  2018; 555(7694): 121-5.
[http://dx.doi.org/10.1038/nature25773] [PMID:  29466332] 
[130] 
Sharma S, Bhatia V. Recent trends in QSAR in Modelling of Drug-Protein and Protein-Protein Interactions. Comb Chem High Throughput Screen 2020.
[131] 
Wootten D, Simms J, Koole C, et al. Modulation of the glucagon-like peptide-1 receptor signaling by naturally occurring and synthetic flavonoids. J Pharmacol Exp Ther  2011; 336(2): 540-50.
[http://dx.doi.org/10.1124/jpet.110.176362] [PMID:  21075839] 
[132] 
Positive RG, Lindsey C.  Morris, et al. Discovery of (S)-2-cyclopentyl-N-((1-isopropylpyrrolidin2-yl)-9-methyl-1-oxo-2,9-dihydro-1H-pyrrido[3,4-b]indole-4-carboxamide (VU0453379): a novel, CNS penetrant glucagon-like peptide 1 receptor (GLP-1R) positive allosteric modulator (PAM). J Med Chem  2014; 57(23): 10192-7.
[PMID: 25423411] 
[133] 
Irwin JJ, Shoichet BK. ZINC-a free database of commercially available compounds for virtual screening. J Chem Inf Model  2005; 45(1): 177-82.
[http://dx.doi.org/10.1021/ci049714+] [PMID:  15667143] 
[134] 
Irwin N, Flatt PR, Patterson S, Green BD. Insulin-releasing and metabolic effects of small molecule GLP-1 receptor agonist 6,7-dichloro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline. Eur J Pharmacol  2010; 628(1-3): 268-73.
[http://dx.doi.org/10.1016/j.ejphar.2009.11.022] [PMID:  19917278] 
[135] 
Bahekar RH, Jain MR, Gupta AA, et al. Synthesis and antidiabetic activity of 3,6,7-trisubstituted-2-(1H-imidazol-2-ylsulfanyl)-quinoxalines and quinoxalin-2-yl isothioureas. Arch Pharm (Weinheim)  2007; 340(7): 359-66.
[http://dx.doi.org/10.1002/ardp.200700024] [PMID:  17567824] 
[136] 
Knudsen SM, Pettersson I, Lau J, Behrens C, Petersen AK, Garibay PW. inventors; Novo Nordisk AS, assignee. Condensed thiophene
	derivatives and their use as cyclic GLP-1 agonists. United
	States patent application US 11/630,007. 2008 Nov 6.. 
[137] 
Liu Q, Li N, Yuan Y, et al. Cyclobutane derivatives as novel nonpeptidic small molecule agonists of glucagon-like peptide-1 receptor. J Med Chem  2012; 55(1): 250-67.
[http://dx.doi.org/10.1021/jm201150j] [PMID:  22103243] 
[138] 
Willard FS, Bueno AB, Sloop KW. Small molecule drug discovery at the glucagon-like peptide-1 receptor. Exp Diabetes Res  2012; 2012709893
[http://dx.doi.org/10.1155/2012/709893] [PMID:  22611375] 
[139] 
Fridlyand LE, Philipson LH. Pancreatic Beta Cell G-Protein Coupled Receptors and Second Messenger Interactions: A Systems Biology Computational Analysis. PLoS One  2016; 11(5)e0152869
[http://dx.doi.org/10.1371/journal.pone.0152869] [PMID:  27138453] 
[140] 
Sang P, Zhou Z, Shi Y, et al. The activity of sulfono-γ-AApeptide helical foldamers that mimic GLP-1. Sci Adv  2020; 6(20)eaaz4988
[http://dx.doi.org/10.1126/sciadv.aaz4988] [PMID:  32440547] 
[141] 
Reese HR, Shanahan CC, Proulx C, Menegatti S. Peptide science: A “rule model” for new generations of peptidomimetics. Acta Biomater  2020; 102: 35-74.
[http://dx.doi.org/10.1016/j.actbio.2019.10.045] [PMID:  31698048] 
[142] 
Tang XM, Hu W, Fan L, Wang H, Tang MH, Yang DC. Synthesis and evaluation of novel peptidomimetics bearing p-aminobenzoic acid moiety as potential antidiabetic agents. Future Med Chem  2020; 12(11): 991-1013.
[http://dx.doi.org/10.4155/fmc-2018-0372] [PMID:  32208864] 
[143] 
Kumar MS. Peptides and peptidomimetics as potential antiobesity agents: Overview of current status. Front Nutr  2019; 6: 11.
[http://dx.doi.org/10.3389/fnut.2019.00011] [PMID:  30834248] 
[144] 
Hoang HN, Song K, Hill TA, et al. Short hydrophobic peptides with cyclic constraints are potent glucagon-like peptide-1 receptor (GLP-1R) agonists. J Med Chem  2015; 58(9): 4080-5.
[http://dx.doi.org/10.1021/acs.jmedchem.5b00166] [PMID:  25839426] 
[145] 
Swedberg JE, Schroeder CI, Mitchell JM, et al. Cyclic alpha-conotoxin peptidomimetic chimeras as potent GLP-1R agonists. Eur J Med Chem  2015; 103: 175-84.
[http://dx.doi.org/10.1016/j.ejmech.2015.08.046] [PMID:  26352676] 
[146] 
Latek D, Rutkowska E, Niewieczerzal S, Cielecka-Piontek J. Drug-induced diabetes type 2: In silico study involving class B GPCRs. PLoS One  2019; 14(1)e0208892
[http://dx.doi.org/10.1371/journal.pone.0208892] [PMID:  30650080] 
[147] 
Day JW, Ottaway N, Patterson JT, et al. A new glucagon and GLP-1 co-agonist eliminates obesity in rodents. Nat Chem Biol  2009; 5(10): 749-57.
[http://dx.doi.org/10.1038/nchembio.209] [PMID:  19597507] 
[148] 
Patterson JT, Day JW, Gelfanov VM, DiMarchi RD. Functional association of the N-terminal residues with the central region in glucagon-related peptides. J Pept Sci  2011; 17(10): 659-66.
[http://dx.doi.org/10.1002/psc.1385] [PMID:  21661079] 
[149] 
Fletcher MM, Halls ML, Zhao P, et al. Glucagon-like peptide-1 receptor internalisation controls spatiotemporal signalling mediated by biased agonists. Biochem Pharmacol  2018; 156: 406-19.
[http://dx.doi.org/10.1016/j.bcp.2018.09.003] [PMID:  30195733] 
[150] 
Hager MV, Clydesdale L, Gellman SH, Sexton PM, Wootten D. Characterization of signal bias at the GLP-1 receptor induced by backbone modification of GLP-1. Biochem Pharmacol  2017; 136: 99-108.
[http://dx.doi.org/10.1016/j.bcp.2017.03.018] [PMID:  28363772] 
[151] 
Hager MV, Johnson LM, Wootten D, Sexton PM, Gellman SH. β-Arrestin-Biased Agonists of the GLP-1 Receptor from β-Amino Acid Residue Incorporation into GLP-1 Analogues. J Am Chem Soc  2016; 138(45): 14970-9.
[http://dx.doi.org/10.1021/jacs.6b08323] [PMID:  27813409] 
[152] 
Zhang H, Sturchler E, Zhu J, et al. Autocrine selection of a GLP-1R G-protein biased agonist with potent antidiabetic effects. Nat Commun  2015; 6: 8918.
[http://dx.doi.org/10.1038/ncomms9918] [PMID:  26621478] 
[153] 
Gigoux V, Fourmy D. Acting on hormone receptors with minimal side effect on cell proliferation: A timely challenge illustrated with GLP-1R and GPER. Front Endocrinol  2013; 4: 50.
[http://dx.doi.org/10.3389/fendo.2013.00050] [PMID:  23641235] 
Cite As
Current Pharmaceutical Design

Drug Design of GLP-1 Receptor Agonists: Importance of In Silico Methods

Abstract
