Exploring the chemical space of peptides for drug discovery: a focus on linear and cyclic penta-peptides


Peptide and peptide-like structures are regaining attention in drug discovery. Previous studies suggest that bioactive peptides have diverse structures and may have physicochemical properties attractive to become hit and lead compounds. However, chemoinformatic studies that characterize such diversity are limited. Herein, we report the physicochemical property profile and chemical space of four synthetic linear and cyclic combinatorial peptide libraries. As a case study, the analysis was focused on penta-peptides. The chemical space of the peptide and N-methylated peptides libraries was compared to compound data sets of pharmaceutical relevance. Results indicated that there is a major overlap in the chemical space of N-methylated cyclic peptides with inhibitors of protein–protein interactions and macrocyclic natural products available for screening. Also, there is an overlap between the chemical space of the synthetic peptides with peptides approved for clinical use (or in clinical trials), and to other approved drugs that are outside the traditional chemical space. Results further support that synthetic penta-peptides are suitable compounds to be used in drug discovery projects.

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  1. 1.

    Henninot A, Collins JC, Nuss JM (2018) The current state of peptide drug discovery: Back to the future? J Med Chem (in press). https://doi.org/10.1021/acs.jmedchem.7b00318

  2. 2.

    Santos GB, Ganesan A, Emery FS (2016) Oral administration of peptide-based drugs: beyond Lipinski’s rule. ChemMedChem 11:2245–2251. https://doi.org/10.1002/cmdc.201600288

    Article  PubMed  CAS  Google Scholar 

  3. 3.

    Bruno BJ, Miller GD, Lim CS (2013) Basics and recent advances in peptide and protein drug delivery. Ther Deliv 4:1443–1467. https://doi.org/10.4155/tde.13.104

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. 4.

    Fosgerau K, Hoffmann T (2015) Peptide therapeutics: current status and future directions. Drug Discov Today 20:122–128. https://doi.org/10.1016/j.drudis.2014.10.003

    Article  PubMed  CAS  Google Scholar 

  5. 5.

    AlMatar M, Makky EA, Yakıcı G, Var I, Kayar B, Köksal F (2017) Antimicrobial peptides as an alternative to anti-tuberculosis drugs. Pharmacol Res. https://doi.org/10.1016/j.phrs.2017.10.011

    PubMed  Article  Google Scholar 

  6. 6.

    van der Does AM, Hensbergen PJ, Bogaards SJ, Cansoy M, Deelder AM, van Leeuwen HC, Drijfhout JW, van Dissel JT, Nibbering PH (2012) The human lactoferrin-derived peptide hlF1-11 exerts immunomodulatory effects by specific inhibition of myeloperoxidase activity. J Immunol 188:5012. https://doi.org/10.4049/jimmunol.1102777

    Article  PubMed  CAS  Google Scholar 

  7. 7.

    Zorzi A, Deyle K, Heinis C (2017) Cyclic peptide therapeutics: past, present and future. Curr Opin Chem Biol 38:24–29. https://doi.org/10.1016/j.cbpa.2017.02.006

    Article  PubMed  CAS  Google Scholar 

  8. 8.

    Ovadia O, Greenberg S, Laufer B, Gilon C, Hoffman A, Kessler H (2010) Improvement of drug-like properties of peptides: the somatostatin paradigm. Expert Opin Drug Discov 5:655–671. https://doi.org/10.1517/17460441.2010.493935

    Article  PubMed  CAS  Google Scholar 

  9. 9.

    Räder AFB, Reichart F, Weinmüller M, Kessler H (2017) Improving oral bioavailability of cyclic peptides by n-methylation. Bioorg Med Chem. https://doi.org/10.1016/j.bmc.2017.08.031

    PubMed  Article  Google Scholar 

  10. 10.

    Nielsen DS, Hoang HN, Lohman R-J, Hill TA, Lucke AJ, Craik DJ, Edmonds DJ, Griffith DA, Rotter CJ, Ruggeri RB, Price DA, Liras S, Fairlie DP (2014) Improving on nature: making a cyclic heptapeptide orally bioavailable. Angew Chemie Int Ed 53:12059–12063. https://doi.org/10.1002/anie.201405364

    Article  CAS  Google Scholar 

  11. 11.

    Madala PK, Tyndall JDA, Nall T, Fairlie DP (2010) Update 1 of: proteases universally recognize beta strands in their active sites. Chem Rev 110:PR1–PR31. https://doi.org/10.1021/cr900368a

    Article  PubMed  CAS  Google Scholar 

  12. 12.

    Houghten RA, Pinilla C, Giulianotti MA, Appel JR, Dooley CT, Nefzi A, Ostresh JM, Yu Y, Maggiora GM, Medina-Franco JL, Brunner D, Schneider J (2008) Strategies for the use of mixture-based synthetic combinatorial libraries: scaffold ranking, direct testing, in vivo, and enhanced deconvolution by computational methods. J Comb Chem 10:3–19. https://doi.org/10.1021/cc7001205

    Article  PubMed  CAS  Google Scholar 

  13. 13.

    Gonzalez MW, Kann MG (2012) Chapter 4: protein interactions and disease. PLoS Comp Biol 8:e1002819. https://doi.org/10.1371/journal.pcbi.1002819

    Article  CAS  Google Scholar 

  14. 14.

    Díaz-Eufracio BI, Naveja JJ, Medina-Franco JL (2018) Protein-protein interaction modulators for epigenetic therapies. Adv Protein Chem Str 110:65–84. https://doi.org/10.1016/bs.apcsb.2017.06.002

    Article  Google Scholar 

  15. 15.

    Fleeman R, LaVoi TM, Santos RG, Morales A, Nefzi A, Welmaker GS, Medina-Franco JL, Giulianotti MA, Houghten RA, Shaw LN (2015) Combinatorial libraries as a tool for the discovery of novel, broad-spectrum antibacterial agents targeting the eskape pathogens. J Med Chem 58:3340–3355. https://doi.org/10.1021/jm501628s

    Article  PubMed  CAS  Google Scholar 

  16. 16.

    Chatterjee J, Gilon C, Hoffman A, Kessler H (2008) N-methylation of peptides: a new perspective in medicinal chemistry. Acc Chem Res 41:1331–1342. https://doi.org/10.1021/ar8000603

    Article  PubMed  CAS  Google Scholar 

  17. 17.

    Rezai T, Bock JE, Zhou MV, Kalyanaraman C, Lokey RS, Jacobson MP (2006) Conformational flexibility, internal hydrogen bonding, and passive membrane permeability? Successful in silico prediction of the relative permeabilities of cyclic peptides. J Am Chem Soc 128:14073–14080. https://doi.org/10.1021/ja063076p

    Article  PubMed  CAS  Google Scholar 

  18. 18.

    Marcucci E, Tulla-Puche J, Albericio F (2012) Solid-phase synthesis of NMe-IB-01212, a highly n-methylated cyclic peptide. Org Lett 14:612–615. https://doi.org/10.1021/ol203231q

    Article  PubMed  CAS  Google Scholar 

  19. 19.

    Team RC R core team (2013). R: A language and environment for statistical computing. R foundation for statistical computing, Vienna, Austria. http://www.R-project.org/. Accessed December 13, 2017

  20. 20.

    Weininger D (1988) SMILES, a chemical language and information system. 1. Introduction to methodology and encoding rules. J Chem Inf Comp Sci 28:31–36. https://doi.org/10.1021/ci00057a005

    Article  CAS  Google Scholar 

  21. 21.

    Law V, Knox C, Djoumbou Y, Jewison T, Guo AC, Liu Y, Maciejewski A, Arndt D, Wilson M, Neveu V, Tang A, Gabriel G, Ly C, Adamjee S, Dame ZT, Han B, Zhou Y, Wishart DS (2014) Drugbank 4.0: shedding new light on drug metabolism. Nucl Acids Res 42:D1091–D1097. https://doi.org/10.1093/nar/gkt1068

    Article  PubMed  CAS  Google Scholar 

  22. 22.

    Labbé CM, Laconde G, Kuenemann MA, Villoutreix BO, Sperandio O (2013) iPPI-DB: a manually curated and interactive database of small non-peptide inhibitors of protein-protein interactions. Drug Discov Today 18:958–968. https://doi.org/10.1016/j.drudis.2013.05.003

    Article  PubMed  CAS  Google Scholar 

  23. 23.

    Chen CY-C (2011) TCM Database@taiwan: the world’s largest traditional chinese medicine database for drug screening in silico. PLoS ONE 6:e15939. https://doi.org/10.1371/journal.pone.0015939

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. 24.

    The Natura Product Company A discovery Collections of purified Natural Products– continuously growing. https://ac-discovery.com/substancelibrary/purified-natural-products/. Accessed 22 Nov 2017

  25. 25.

    The Natural Product Company A discovery Natural Macrocyclic Compounds. https://ac-discovery.com/substancelibrary/natural-macrocyclic-compounds/. Accessed 22 Nov 2017

  26. 26.

    Molecular Operating Environment (MOE), Version 2015.08, Chemical Computing Group INC., Montreal, Quebec. http://www.chemcomp.com

  27. 27.

    Lipinski CA (2004) Lead- and drug-like compounds: the rule-of-five revolution. Drug Discov Today: Technologies 1:337–341. https://doi.org/10.1016/j.ddtec.2004.11.007

    Article  PubMed  CAS  Google Scholar 

  28. 28.

    Prieto-Martinez FD, Gortari EF, Mendez-Lucio O, Medina-Franco JL (2016) A chemical space odyssey of inhibitors of histone deacetylases and bromodomains. RSC Adv 6:56225–56239. https://doi.org/10.1039/C6RA07224K

    Article  CAS  Google Scholar 

  29. 29.

    Olmedo DA, González-Medina M, Gupta MP, Medina-Franco JL (2017) Cheminformatic characterization of natural products from panama. Molecular Divers 21:779–789. https://doi.org/10.1007/s11030-017-9781-4

    Article  CAS  Google Scholar 

  30. 30.

    Medina-Franco JL, Maggiora GM (2014) Molecular similarity analysis. In: Bajorath J (ed) Chemoinformatics for drug discovery. Wiley, New York, pp 343–399. https://doi.org/10.1002/9781118742785.ch15

    Google Scholar 

  31. 31.

    Bajusz D, Rácz A, Héberger K (2015) Why is tanimoto index an appropriate choice for fingerprint-based similarity calculations? J Cheminf 7:1–13. https://doi.org/10.1186/s13321-015-0069-3

    Article  CAS  Google Scholar 

  32. 32.

    Berthold MR, Cebron N, Dill F, Gabriel TR, Kötter T, Meinl T, Ohl P, Sieb C, Thiel K, Wiswedel B (2008) KNIME: the Konstanz information miner. In: Preisach C, Burkhardt H, Schmidt-Thieme L (eds) Data analysis, machine learning and applications, studies in classification, data analysis, and knowledge organization. Springer, Berlin, pp 319–326. https://doi.org/10.1007/978-3-540-78246-9_38

    Google Scholar 

  33. 33.

    Chikako O, Yuen-Joyce L, Koichi SK (2011) Muramyl dipeptide and its derivatives: peptide adjuvant in immunological disorders and cancer therapy. Curr Bioactive Compds 7:180–197. https://doi.org/10.2174/157340711796817913

    Article  Google Scholar 

  34. 34.

    Kim Y-H, Lee JK, Kim B, DeWitt JP, Lee JE, Han JH, Kim SK, Oh CW, Kim CY (2013) Combination therapy of cilengitide with belotecan against experimental glioblastoma. Int J Cancer 133:749–756. https://doi.org/10.1002/ijc.28058

    Article  PubMed  CAS  Google Scholar 

  35. 35.

    Belema M, Nguyen VN, Bachand C, Deon DH, Goodrich JT, James CA, Lavoie R, Lopez OD, Martel A, Romine JL, Ruediger EH, Snyder LB, St Laurent DR, Yang F, Zhu J, Wong HS, Langley DR, Adams SP, Cantor GH, Chimalakonda A, Fura A, Johnson BM, Knipe JO, Parker DD, Santone KS, Fridell RA, Lemm JA, O’Boyle DR 2nd, Colonno RJ, Gao M, Meanwell NA, Hamann LG (2014) Hepatitis C virus nS5A replication complex inhibitors: the discovery of daclatasvir. J Med Chem 57:2013–2032. https://doi.org/10.1021/jm401836p

    Article  PubMed  CAS  Google Scholar 

  36. 36.

    López-Vallejo F, Giulianotti MA, Houghten RA, Medina-Franco JL (2012) Expanding the medicinally relevant chemical space with compound libraries. Drug Discov Today 17:718–726. https://doi.org/10.1016/j.drudis.2012.04.001

    Article  PubMed  CAS  Google Scholar 

  37. 37.

    Medina-Franco JL, Martínez-Mayorga K, Bender A, Marín RM, Giulianotti MA, Pinilla C, Houghten RA (2009) Characterization of activity landscapes using 2D and 3D similarity methods: consensus activity cliffs. J Chem Inf Model 49:477–491. https://doi.org/10.1021/ci800379q

    Article  PubMed  CAS  Google Scholar 

  38. 38.

    Medina-Franco JL, Martinez-Mayorga K, Meurice N (2014) Balancing novelty with confined chemical space in modern drug discovery. Expert Opin Drug Discovery 9:151–165. https://doi.org/10.1517/17460441.2014.872624

    Article  CAS  Google Scholar 

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B.I.D.-E. and O.P. acknowledges Consejo Nacional de Ciencia y Tecnología (CONACyT) for Scholarships Number 620289 and 606003, respectively. This work was supported by the Programa de Apoyo a la Investigación y el Posgrado (PAIP) Grant 5000-9163, Facultad de Química, UNAM. This work is dedicated to the loving memory of Nicolás Medina Sandoval.

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Correspondence to José L. Medina-Franco.

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Díaz-Eufracio, B.I., Palomino-Hernández, O., Houghten, R.A. et al. Exploring the chemical space of peptides for drug discovery: a focus on linear and cyclic penta-peptides. Mol Divers 22, 259–267 (2018). https://doi.org/10.1007/s11030-018-9812-9

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  • Cheminformatics
  • Chemical space
  • Combinatorial chemistry
  • Protein–protein inhibitors
  • Small molecules
  • Synthetic peptides