Advertisement

Binding free energy calculations of N-sulphonyl-glutamic acid inhibitors of MurD ligase

Abstract

The increasing incidence of bacterial resistance to most available antibiotics has underlined the urgent need for the discovery of novel efficacious antibacterial agents. The biosynthesis of bacterial peptidoglycan, where the MurD enzyme is involved in the intracellular phase of UDP-MurNAc-pentapeptide formation, represents a collection of highly selective targets for novel antibacterial drug design. Structural studies of N-sulfonyl-glutamic acid inhibitors of MurD have made possible the examination of binding modes of this class of compounds, providing valuable information for the lead optimization phase of the drug discovery cycle. Binding free energies were calculated for a series of MurD N-sulphonyl-Glu inhibitors using the linear interaction energy (LIE) method. Analysis of interaction energy during the 20-ns MD trajectories revealed non-polar van der Waals interactions as the main driving force for the binding of these inhibitors, and excellent agreement with the experimental free energies was obtained. Calculations of binding free energies for selected moieties of compounds in this structural class substantiated even deeper insight into the source of inhibitory activity. These results constitute new valuable information to further assist the lead optimization process.

This is a preview of subscription content, log in to check access.

Access options

Buy single article

Instant unlimited access to the full article PDF.

US$ 39.95

Price includes VAT for USA

Subscribe to journal

Immediate online access to all issues from 2019. Subscription will auto renew annually.

US$ 199

This is the net price. Taxes to be calculated in checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Notes

  1. 1.

    or corresponding hydrogen in compound 5

References

  1. 1.

    Silver LL (2006) Does the cell wall of bacteria remain a viable source of targets for novel antibiotics? Biochem Pharmacol 71:996–1005

  2. 2.

    Brown ED, Wright GD (2005) New targets and screening approaches in antimicrobial drug discovery. Chem Rev 105:759–774

  3. 3.

    Vollmer W, Blanot D, de Pedro MA (2008) Peptidoglycan structure and architecture. FEMS Microbiol Rev 32:149–167

  4. 4.

    Barreteau H, Kovač A, Boniface A, Sova M, Gobec S, Blanot D (2008) Cytoplasmic steps of peptidoglycan biosynthesis. FEMS Microbiol Rev 32:168–207

  5. 5.

    van Heijenoort J (2001) Recent advances in the formation of the bacterial peptidoglycan monomer unit. Nat Prod Rep 18:503–519

  6. 6.

    Smith CS (2006) Structure, function and dynamics in the mur family of bacterial cell wall ligases. J Mol Biol 362:640–655

  7. 7.

    Bertrand JA, Auger G, Martin L, Fanchon E, Blanot D, Le Beller D, van Heijenoort J, Dideberg O (1999) Determination of the MurD mechanism through crystallographic analysis of enzyme complexes. J Mol Biol 289:579–590

  8. 8.

    Anderson MS, Eveland SS, Onishi H, Pompliano DL (1996) Kinetic mechanism of the Escherichia coli UDPMurNAc-tripeptide D-alanyl-D-alanine-adding enzyme: use of a glutathione S-transferase fusion. Biochemistry 35:16264–16269

  9. 9.

    Emanuele JJ Jr, Jin H, Yanchunas J , Villafranca JJ (1997) Evaluation of the kinetic mechanism of Escherichia coli uridine diphosphate-N-acetylmuramate:L-alanine ligase. Biochemistry 36:7264–7271

  10. 10.

    Perdih A, Hodoscek M, Solmajer T (2009) MurD ligase from E. coli: Tetrahedral intermediate formation study by hybrid quantum mechanical/molecular mechanical replica path method. Proteins: Structure Funct Bioinf 74:744–759

  11. 11.

    Bouhss A, Dementin S, van Heijenoort J, Parquet C, Blanot D (2002) MurC and MurD synthetases of peptidoglycan biosynthesis: Borohydride trapping of acyl-phosphate intermediates. Methods in Enzymology 354:189–196

  12. 12.

    Falk PJ, Ervin KM, Volk KS, Ho H-T (1996) Biochemical evidence for the formation of a covalent acyl-phosphate linkage between UDP-N-Acetylmuramate and ATP in the Escherichia coli UDP-N-acetylmuramate:L-alanine ligase-catalyzed reaction. Biochemistry 35:1417–1422

  13. 13.

    Bertrand JA, Fanchon E, Martin L, Chantalat L, Auger G, Blanot D, van Heijenoort J, Dideberg O (2000) “Open” structures of MurD: domain movements and structural similarities with folylpolyglutamate synthetase. J Mol Biol 301:1257–1266

  14. 14.

    Perdih A, Kotnik M, Hodoscek M, Solmajer T (2007) Targeted Molecular Dynamics Simulation Studies of Binding and Conformational Changes in E.Coli MurD. Proteins: Structure Funct Bioinf 68:243–254

  15. 15.

    Zoeiby AE, Sanschagrin F, Levesque RC (2002) Structure and function of the Mur enzymes: Development of novel Inhibitors. Mol Microbiol 47:1–12

  16. 16.

    Tanner ME, Vaganay S, van Heijenoort J, Blanot D (1996) Phosphinate inhibitors of the D-glutamic acid-adding enzyme of peptidoglycan biosynthesis. J Org Chem 61:1756–1760

  17. 17.

    Štrancar K, Blanot D, Gobec S (2006) Design, synthesis and structure–activity relationships of new phosphinate inhibitors of MurD. Bioorg Med Chem 16:343–348

  18. 18.

    Humljan J, Kotnik M, Boniface A, Šolmajer T, Urleb U, Blanot D, Gobec S (2006) A new approach towards peptidosulfonamides: synthesis of potential inhibitors of bacterial peptidoglycan biosynthesis enzymes MurD and MurE. Tetrahedron 62:10980–10988

  19. 19.

    Humljan J (2007) Design, synthesis and characterization of new sulfonamide inhibitors of Mur ligases. PhD dissertation Ljubljana

  20. 20.

    Humljan J, Kotnik M, Contreras-Martel C, Blanot D, Urleb U, Desssen A, Solmajer T, Gobec S (2008) Novel naphtalene –N-sulfonyl-D-glutamic acid derivatives as inhibitors of MurD, a key peptidoglycan biosynthesis enzyme. J Med Chem 51:7486–7494

  21. 21.

    Pratviel-Sosa F, Acher F, Trigalo F, Blanot D, Azerad R, van Heijenoort J (1994) Effect of various analogues of D-glutamic acid on the D-glutamate-adding enzyme from Escherichia coli. FEMS Microbiol Lett 115:223–228

  22. 22.

    Kotnik M (2007) Computer-Aided and Structure-Based Design of Novel Inhibitors of Mur Ligases. PhD dissertation Ljubljana

  23. 23.

    Kotnik M, Humljan J, Contreras-Martel C, Oblak M, Kristan K, Hervé M, Blanot D, Urleb U, Gobec S, Dessen A, Solmajer T (2007) Structural and functional characterization of enantiomeric glutamic acid derivatives as potential transition state analogue inhibitors of MurD ligase. J Mol Biol 370:107–115

  24. 24.

    Obreza A, Gobec S (2004) Recent advances in design, synthesis and biological activity of aminoalkylsulfonates and sulfonamidopeptides. Curr Med Chem 11:3263–3278

  25. 25.

    Jorgensen WL (2004) The Many Roles of Computation in Drug Discovery. Science 303:1813–1818

  26. 26.

    Klebe G (2006) Virtual ligand screening: strategies, perspectives and limitations. Drug Discovery Today 11:580–594

  27. 27.

    Schneider G, Böhm H-J (2002) Virtual screening and fast automated docking methods. Drug Discovery Today 7:64–70

  28. 28.

    Wolber G, Langer T (2005) LigandScout: 3-D pharmacophores derived from protein-bound ligands and their use as virtual screening filters. J Chem Inf Model 45:160–169

  29. 29.

    Kollman PA (1993) Free energy calculations: Applications to chemical and biochemical phenomena. Chem Rev 93:2395–2417

  30. 30.

    Chen X, Tropsha A (2006) Calculation of the relative binding affinity of enzyme inhibitors using the generalized linear response method. J Chem Theory and Comput 2:1435–1443

  31. 31.

    Åqvist J, Medina C, Samuelson JE (1994) A new method for predicting binding affinity in computer-aided drug design. Protein Eng 7:385–391

  32. 32.

    Åqvist J, Luzhkov VB, Brandsdal BO (2002) Ligand Binding Affinities from MD Simulations. Acc Chem Res 35:358–365

  33. 33.

    Florián J, Goodman MF, Warshel A (2002) Theoretical investigation of the binding free energies and key substrate-recognition components of the replication fidelity of human DNA polymerase β. J Phys Chem B 106:5739–5753

  34. 34.

    Lee FS, Chu Z-T, Bolger MB, Warshel A (1992) Calculations of antibody-antigen interactions: microscopic and semi-microscopic evaluation of the free energies of binding of phosphorylcholine analogs to McPC603. Protein Eng 5:215–228

  35. 35.

    Bren U, Martinek V, Florian J (2006) Free energy simulations of uncatalyzed DNA replication fidelity: Structure and stability of T·G and dTTP·G terminal DNA mismatches flanked by a single dangling nucleotide. J Phys Chem B 110:10557–10566

  36. 36.

    Carlson HA, Jorgensen WL (1995) An extended linear response method for determining free energies of hydration. J Phys Chem 99:10667–10673

  37. 37.

    Zhou RH, Friesner RA, Ghosh A, Rizzo RC, Jorgensen WL, Levy RM (2001) New Linear interaction method for binding affinity calculations using a continuum solvent model. J Phys Chem B 105:10388–10397

  38. 38.

    Smith RH, Jorgensen WL, Tirado-Rives J, Lamb ML, Janssen PAJ, Michejda CJ, Smith MBK (1998) Prediction of binding affinities for TIBO inhibitors of HIV-1 reverse transcriptase using Monte Carlo simulations in a linear response method. J Med Chem 41:5272–5286

  39. 39.

    Hansson T, Marelius J, Aquist J (1998) Ligand binding affinity prediction by linear interaction energy methods. J Comp–Aid Mol Des 12:27–35

  40. 40.

    Carlson J, Boukharta L, Aquist J (2008) Combining Docking, Molecular Dynamics and the Linear Interaction Energy Method to Predict Binding Modes and Affinities for Non-nucleoside Inhibitors to HIV-1 Reverse Transcriptase. J Med Chem 51:2648–2656

  41. 41.

    Kolb P, Huang D, Dey F, Caflisch A (2008) Discovery of kinase inhibitors by high-throughput docking and scoring based on a transferable linear interaction energy model. J Med Chem 51:1179–1188

  42. 42.

    Bortolato A, Moro S (2007) In silico binding free energy predictability by using the linear interaction energy (LIE) method: Bromobenzimidazole CK2 inhibitors as a case study. J Chem Inf Model 47:572–582

  43. 43.

    Foloppe N, Hubbard R (2006) Towards predictive ligand design with free-energy based computational methods? Curr Med Chem 13:3583–3608

  44. 44.

    Bren M, Florián J, Mavri J, Bren U (2007) Do all pieces make a whole? Thiele cumulants and the free energy decomposition. Theor Chem Acc 117:535–540

  45. 45.

    http://www.pdb.org/pdb/.

  46. 46.

    Borštnik U, Hodošček M, Janežič D (2004) Improving the performance of molecular dynamics simulations on parallel clusters. J Chem Inf Comput Sci 44:359–364

  47. 47.

    Marelius J, Kolmodin K, Feierberg I, Åqvist J (1999) A molecular dynamics program for free energy calculations and empirical valence bond simulations in biomolecular systems. J Mol Graphics Model 16:213–225

  48. 48.

    Cornell WD, Cieplak P, Bayly CI, Gould IR, Merz M Jr, Ferguson DM, Spellmeyer DC, Fox T, Caldwell JW, Kollman PA (1995) A second generation force field for the simulation of proteins, nucleic acids, and organic molecules. J Am Chem Soc 117:5179–5197

  49. 49.

    Spartan 5.0 Wavefunction In Irvine CA USA

  50. 50.

    Gaussian 03 Revision C.02 Frisch M J, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Montgomery J A, Vreven T Jr, Kudin KN, Burant JC, Millam JM, Iyengar SS, Tomasi J, Barone V, Mennucci B, Cossi M, Scalmani G, Rega N, Petersson GA, Nakatsuji H, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Klene M, Li X, Knox JE, Hratchian HP, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Ayala PY, Morokuma K, Voth GA, Salvador P, Dannenberg JJ, Zakrzewski VG, Dapprich S, Daniels AD, Strain MC, Farkas O, Malick DK, Rabuck AD, Raghavachari K, Foresman JB, Ortiz JV, Cui Q, Baboul AG, Clifford S, Cioslowski J, Stefanov BB, Liu G, Liashenko A, Piskorz P, Komaromi I, Martin RL, Fox DJ, Keith T, Al-Laham MA, Peng CY, Nanayakkara A, Challacombe M, Gill PMW, Johnson B, Chen W, Wong MW, Gonzalez C, Pople JA Gaussian Inc., Wallingford, CT 2004

  51. 51.

    Bren U, Hodoscek M, Koller J (2005) Development and Validation of Empirical Force Field Parameters for Netropsin. J Chem Inf Model 45:1546–1552

  52. 52.

    Bayly CI, Cieplak P, Cornell WD, Kollman PA (1993) A well-behaved electrostatic potential based method using charge restrains for deriving atomic charges: The RESP Model. J Phys Chem 97:10269–10280

  53. 53.

    Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein ML (1983) Comparison of simple potential functions for simulating liquid water. J Chem Phys 79:926–935

  54. 54.

    King G, Warshel A (1989) A surface constrained all-atom solvent model for effective simulations of polar solutions. J Chem Phys 91:3647–3661

  55. 55.

    Lee FS, Warshel A (1992) A local reaction field method for fast evaluation of long-range electrostatic interactions in molecular simulations. J Chem Phys 97:3100–3107

  56. 56.

    Handler N, Brunhofer G, Studenik C, Leisser K, Jaeger W, Parth S, Erker T (2007) ‘Bridged’ stilbene derivatives as selective cyclooxygenase-1 inhibitors. Bioorg Med Chem 15:6109–6118

  57. 57.

    Humphrey W, Dalke A, Schulten K (1996) VMD: visual molecular dynamics. J Mol Graph 14:33–38

  58. 58.

    Gramatica P (2007) Principles of QSAR models validation: internal and external. QSAR Comb Sci 26:694–701

Download references

Acknowledgements

The authors thank Dr. Milan Hodošček for helpful technical assistance. The financial support of the Slovenian Ministry of Science and Higher Education through Grant P1-0012 is gratefully acknowledged.

Author information

Correspondence to Tom Solmajer.

Additional information

Andrej Perdih and Urban Bren contributed equally to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Bound_state (MPG 6.96 MB)

Free_state (MPG 6.96 MB)

Supplementary Material

(a) Tables of partial atomic charges and atom types of N-sulfonyl-D-glutamic acid derivatives 1–12 and side chain of carbamylated Lys198 (KCX moiety). (b) The time dependence of all distances monitored along the 20 ns MD trajectories. (c) RMSD plots of conformations of inhibitors 1 and 2 produced during the MD simulations with respect to their conformations in the crystal structures. (d) Interaction energy between compound 3 and its surrounding (water and sodium ions in the free state (blue) and water, sodium ions and protein in the bound state (red)) during the 20 ns MD simulation. (e) Two animations presenting bound and free state of compound 4 during the MD simulation (PDF 6.96 MB)

Bound_state (MPG 6.96 MB)

Free_state (MPG 6.96 MB)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Perdih, A., Bren, U. & Solmajer, T. Binding free energy calculations of N-sulphonyl-glutamic acid inhibitors of MurD ligase. J Mol Model 15, 983–996 (2009) doi:10.1007/s00894-009-0455-8

Download citation

Keywords

  • Antibacterial agents
  • Drug design
  • Linear interaction energy (LIE) method
  • Molecular dynamics (MD) simulations
  • MurD ligase
  • N-sulfonyl-glutamic acid derivatives