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CoMFA and CoMSIA of diverse pyrrolidine analogues as dipeptidyl peptidase IV inhibitors: active site requirements

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Abstract

The inhibition of dipeptidyl peptidase IV (DPP-IV) has emerged as an attractive target in the treatment of type 2 diabetes. In view of this development, a critical analysis of structural requirements of the DPP-IV inhibitors is envisioned to identify the significant features toward design of selective inhibitors. The comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) contour plots of pyrrolidine based analogues are used to analyze the structural requirements of a DPP-IV active site. The CoMFA model has shown a cross-validated q 2 of 0.651 with a non-cross-validated r 2 of 0.882 and explained 70.6% variance in the activity of external test compounds. In this, the steric and electrostatic fields have respectively contributed 59.8 and 40.2%, respectively, to the explained activity of the compounds. The CoMSIA model has shown optimum predictivity (cross-validated q 2 = 0.661; non-cross-validated r 2 = 0.803; external test set’s predictive r 2 = 0.706) with four molecular fields namely, steric, electrostatic, hydrogen bond (HB)-donor, and HB-acceptor. The contour plots of molecular fields resulting from these studies have suggested: (i) steric restriction with small electron rich substituent at 2- and 3-position of pyrrolidine ring, (ii) presence of electropositive ring linker between the pyrrolidine head and aryl tail, (iii) presence of electron-rich groups around the aryl tail moiety, and (iv) presence of sulfonamide between the ring linker and aryl tail which would increase DPP-IV binding affinity of the compounds. These findings will help in the design of structurally related/new compounds as potential DPP-IV inhibitors.

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Abbreviations

CoMFA:

Comparative molecular field analysis

CoMSIA:

Comparative molecular similarity indices analysis

GLP-1:

Glucagon-like peptide 1

DPP:

Dipeptidyl peptidase

PLS:

Partial least-squares

References

  1. Creutzfeldt W (1979) The incretin concept today. Diabetologia 16: 75–85. doi:10.1007/BF01225454

    Article  PubMed  CAS  Google Scholar 

  2. Knudsen LB (2004) Glucagon-like peptide-1: the basis of a new class of treatment for type 2 diabetes. J Med Chem 47: 4128–4134. doi:10.1021/jm030630m

    Article  PubMed  CAS  Google Scholar 

  3. Weber AE (2004) Dipeptidyl peptidase IV Inhibitors for the treatment of diabetes. J Med Chem 47: 4135–4141. doi:10.1021/jm030628v

    Article  PubMed  CAS  Google Scholar 

  4. Augustyns K, Van der Veken P, Senten K, Haemers A (2005) The therapeutic potential of inhibitors of dipeptidyl peptidase IV (DPP IV) and related proline-specific dipeptidyl aminopeptidases. Curr Med Chem 12: 971–998. doi:10.2174/0929867053507298

    Article  PubMed  CAS  Google Scholar 

  5. Augustyns K, Van der Veken P, Haemers A (2005) Inhibitors of proline-specific dipeptidyl peptidases: DPP-IV inhibitors as novel approach for the treatment of type 2 diabetes. Expert Opin Ther Pat 15: 1387–1407. doi:10.1517/13543776.15.10.1387

    Article  CAS  Google Scholar 

  6. Geldern TWV, Trevillyan JM (2006) ‘The next big thing’ in diabetes: clinical progress on DPP-IV Inhibitors. Drug Dev Res 67: 627–642. doi:10.1002/ddr.20138

    Article  Google Scholar 

  7. Orskov C (1992) Glucagon-like peptide-1, a new hormone of the entero-insular axis. Diabetologia 35: 701–711. doi:10.1007/BF00429088

    PubMed  CAS  Google Scholar 

  8. Zander M, Madsbad S, Madsen JL, Holst JJ (2002) Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and β-cell function in type 2 diabetes: a parallel-group study. Lancet 359: 824–830. doi:10.1016/S0140-6736(02)07952-7

    Article  PubMed  CAS  Google Scholar 

  9. Meier JJ, Nauck MA (2005) Glucagon-like peptide 1 (GLP-1) in biology and pathology. Diabetes Metab Res Rev 21: 91–117. doi:10.1002/dmrr.538

    Article  PubMed  CAS  Google Scholar 

  10. Combettes MMJ (2006) GLP-1 and type 2 diabetes: physiology and new clinical advances. Curr Opin Pharm 6: 598–605. doi:10.1016/j.coph.2006.08.003

    Article  CAS  Google Scholar 

  11. Havale SH, Pal M (2009) Medicinal chemistry approaches to the inhibition of dipeptidyl peptidase-4 for the treatment of type 2 diabetes. Bioorg Med Chem Lett 17: 1783–1802. doi:10.1016/j.bmc.2009.01.061

    Article  CAS  Google Scholar 

  12. Hansch C (1981) The physicochemical approach to drug design and discovery (QSAR). Drug Dev Res 1: 267–309. doi:10.1002/ddr.430010403

    Article  CAS  Google Scholar 

  13. Kubinyi H (1997) QSAR and 3D-QSAR in drug design. Part 1: methodology. Drug Discov Today 2: 457–467. doi:10.1016/S1359-6446(97)01079-9

    Article  CAS  Google Scholar 

  14. Murugesan V, Prabhakar YS, Katti SB (2009) CoMFA and CoMSIA studies on thiazolidin-4-one as anti-HIV-1 agents. J Mol Graph Model 27: 735–743. doi:10.1016/j.jmgm.2008.11.006

    Article  PubMed  CAS  Google Scholar 

  15. Pissurlenkar RRS, Shaikh MS, Coutinho EC (2007) 3D-QSAR studies of dipeptidyl peptidase IV inhibitors using a docking based alignment. J Mol Model 13: 1047–1071. doi:10.1007/s00894-007-0227-2

    Article  PubMed  CAS  Google Scholar 

  16. Zeng J, Liu G, Tang Y, Jiang H (2007) 3D-QSAR studies on fluoropyrrolidine amides as dipeptidyl peptidase IV inhibitors by CoMFA and CoMSIA. J Mol Model 13: 993–1000. doi:10.1007/s00894-007-0221-8

    Article  PubMed  CAS  Google Scholar 

  17. Kang NS, Ahn JH, Kim SS, Chae CH, Yoo SE (2007) Docking-based 3D-QSAR study for selectivity of DPP4, DPP8, and DPP9 inhibitors. Bioorg Med Chem Lett 17: 3716–3721. doi:10.1016/j.bmcl.2007.04.031

    Article  PubMed  CAS  Google Scholar 

  18. Gao YD, Feng D, Sheridan RP, Scapin G, Patel SB, Wu JK, Zhang X, SinhaRoy R, Thornberry NA, Weberb AE, Biftu T (2007) Modeling assisted rational design of novel, potent, and selective pyrrolopyrimidine DPP-4 inhibitors. Bioorg Med Chem Lett 17: 3877–3879. doi:10.1016/j.bmcl.2007.04.106

    Article  PubMed  CAS  Google Scholar 

  19. Parmee ER, He J, Mastracchio A, Edmondson SD, Colwell L, Eiermann G, Feeney WP, Habulihaz B, He H, Kilburn R, Leiting B, Lyons K, Marsilio F, Patel RA, Petrov A, Di Salvo J, Wu JK, Thornberry NA, Weber AE (2004) 4-Amino cyclohexylglycine analogues as potent dipeptidylpeptidase IV inhibitors. Bioorg Med Chem Lett 14: 43–46. doi:10.1016/j.bmcl.2003.10.016

    Article  PubMed  CAS  Google Scholar 

  20. Ashton WT, Dong H, Sisco RM, Doss GA, Leiting B, Patel RA, Wu JK, Marsilio F, Thornberry NA, Weber AE (2004) Diastereoselective synthesis and configuration-dependent activity of (3-substituted-cycloalkyl)glycine pyrrolidides and thiazolidides as dipeptidyl peptidase IV inhibitors. Bioorg Med Chem Lett 14: 859–863. doi:10.1016/j.bmcl.2003.12.013

    Article  PubMed  CAS  Google Scholar 

  21. Lu IL, Lee SJ, Tsu H, Wu SY, Kao KH, Chien CH, Chang YY, Chen YS, Cheng JH, Chang CN, Chen TW, Chang SP, Chen X, Jiaang WT (2005) Glutamic acid analogues as potent dipeptidyl peptidase IV and 8 inhibitors. Bioorg Med Chem Lett 15: 3271–3275. doi:10.1016/j.bmcl.2005.04.051

    Article  PubMed  CAS  Google Scholar 

  22. Xu J, Wei L, Mathvink R, Edmondson SD, Mastracchio A, Eiermann GJ, He H, Leone JF, Leiting B, Lyons KA, Marsilio F, Patel RA, Petrov A, Wu JK, Thornberry NA, Weber AE (2006) Discovery of potent, selective, and orally bioavailable pyridone-based dipeptidyl peptidase-4 inhibitors. Bioorg Med Chem Lett 16: 1346–1349. doi:10.1016/j.bmcl.2005.11.052

    Article  PubMed  CAS  Google Scholar 

  23. Xu J, Wei L, Mathvink RJ, Edmondson SD, Eiermann GJ, He H, Leone JF, Leiting B, Lyons KA, Marsilio F, Patel RA, Patel SB, Petrov A, Scapin G, Wu JK, Thornberry NA, Weber AE (2006) Discovery of potent, selective, and orally bioavailable oxadiazole-based dipeptidyl peptidase IV Inhibitors. Bioorg Med Chem Lett 16: 5373–5377. doi:10.1016/j.bmcl.2006.07.061

    Article  PubMed  CAS  Google Scholar 

  24. Edmondson SD, Mastracchio A, Mathvink RJ, He J, Harper B, Park YJ, Beconi M, Di Salvo J, Eiermann GJ, He H, Leiting B, Leone JF, Levorse DA, Lyons K, Patel RA, Patel SB, Petrov A, Scapin G, Shang J, Roy RS, Smith A, Wu JK, Xu S, Zhu B, Thornberry NA, Weber AE (2006) (2S,3S)-3-amino-4-(3,3-difluoropyrrolidin-1-yl)-N, N-dimethyl-4- oxo-2- (4 -[1, 2, 4]triazolo [1,5-a]-pyridin-6-ylphenyl)butanamide: a selective α-amino amide dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J Med Chem 49: 3614–3627. doi:10.1021/jm060015t

    Article  PubMed  CAS  Google Scholar 

  25. Duffy JL, Kirk BA, Wang L, Eiermann GJ, He H, Leiting B, Lyons KA, Patel RA, Patel SB, Petrov A, Scapin G, Wu JK, Thornberry NA, Weber AE (2007) 4-Aminophenylalanine and 4-aminocyclohexylalanine derivatives as potent, selective, and orally bioavailable inhibitors of dipeptidyl peptidase IV. Bioorg Med Chem Lett 17: 2879–2885. doi:10.1016/j.bmcl.2007.02.066

    Article  PubMed  CAS  Google Scholar 

  26. Leiting B, Pryor KD, Wu JK, Marsilio F, Patel RA, Craik CS, Ellman JA, Cummings RT, Thornberry NA (2003) Catalytic properties and inhibition of proline-specific dipeptidyl peptidases II, IV and VII. Biochem J 371: 525–532. doi:10.1042/BJ20021643

    Article  PubMed  CAS  Google Scholar 

  27. MOE: The Molecular Operating Environment from Chemical Computing Group Inc., 1255 University Street, Suite 1600, Montreal, Quebec, Canada H3B 3X3

  28. SYBYL, version 7.3; Tripos associates. St. Louis, MO, USA, 2006

  29. Clark M, Cramer RD III, Opdenbosch NV (1989) Validation of the general purpose tripos 5.2 force field. J Comput Chem 10: 982–1012. doi:10.1002/jcc.540100804

    Article  CAS  Google Scholar 

  30. Nyburg SC (1974) Some uses of a best molecular fit routine. Acta Crystallogr B 30: 251–253. doi:10.1107/S0567740874002603

    Article  CAS  Google Scholar 

  31. Cramer RD III, Patterson DE, Bunce JD (1988) Comparative molecular field analysis (CoMFA). 1. Effect of shape on binding of steroids to carrier proteins. J Am Chem Soc 110: 5959–5967. doi:10.1021/ja00226a005

    Article  CAS  Google Scholar 

  32. Klebe G, Abraham U, Mietzner T (1994) Molecular similarity indices in a comparative analysis (CoMSIA) of drug molecules to correlate and predict their biological activity. J Med Chem 37: 4130–4146. doi:10.1021/ja00226a005

    Article  PubMed  CAS  Google Scholar 

  33. Stahle L, Wold S (1988) 6 Multivariate data analysis and experimental design in biomedical research. Prog Med Chem 25: 291–338. doi:10.1016/S0079-6468(08)70281-9

    Article  PubMed  CAS  Google Scholar 

  34. Cramer RD III, Bunce JD, Patterson DE, Frank IE (1988) Crossvalidation, bootstrapping, and partial least squares compared with multiple regression in conventional QSAR studies. Quant Struct Act Relat 7: 18–25. doi:10.1002/qsar.19880070105

    Article  Google Scholar 

  35. Golbraikh A, Tropsha A (2002) Beware of q2. J Mol Graph Model 20: 269–276. doi:10.1016/S1093-3263(01)00123-1

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow, 226001, India

    Vanangamudi Murugesan, Nidhi Sethi, Yenamandra S. Prabhakar & Seturam B. Katti

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  1. Vanangamudi Murugesan
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  2. Nidhi Sethi
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  3. Yenamandra S. Prabhakar
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  4. Seturam B. Katti
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Correspondence to Seturam B. Katti.

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Murugesan, V., Sethi, N., Prabhakar, Y.S. et al. CoMFA and CoMSIA of diverse pyrrolidine analogues as dipeptidyl peptidase IV inhibitors: active site requirements. Mol Divers 15, 457–466 (2011). https://doi.org/10.1007/s11030-010-9267-0

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