Design of novel ligands of CDP-methylerythritol kinase by mimicking direct protein-protein and solvent-mediated interactions
Victor Giménez-Oya
Department de Bioquímica i Biología Molecular, Universitat de Barcelona (UB), Avda Diagonal 645, E-08028 Barcelona, Spain
Search for more papers by this authorÓscar Villacañas
Department de Química Física, Universitat de Barcelona (UB) and the Institut de Recerca en Química Teòrica i Computacional (IQTCUB), Martí i Franquès 1, E-08028 Barcelona, Spain
Search for more papers by this authorCristian Obiol-Pardo
Department de Química Física, Universitat de Barcelona (UB) and the Institut de Recerca en Química Teòrica i Computacional (IQTCUB), Martí i Franquès 1, E-08028 Barcelona, Spain
Search for more papers by this authorMeritxell Antolin-Llovera
Department de Bioquímica i Biología Molecular, Universitat de Barcelona (UB), Avda Diagonal 645, E-08028 Barcelona, Spain
Search for more papers by this authorJaime Rubio-Martinez
Department de Química Física, Universitat de Barcelona (UB) and the Institut de Recerca en Química Teòrica i Computacional (IQTCUB), Martí i Franquès 1, E-08028 Barcelona, Spain
Search for more papers by this authorCorresponding Author
Santiago Imperial
Department de Bioquímica i Biología Molecular, Universitat de Barcelona (UB), Avda Diagonal 645, E-08028 Barcelona, Spain
Department de Bioquímica i Biología Molecular, Universitat de Barcelona (UB), Avda Diagonal 645, E-08028 Barcelona, Spain.Search for more papers by this authorVictor Giménez-Oya
Department de Bioquímica i Biología Molecular, Universitat de Barcelona (UB), Avda Diagonal 645, E-08028 Barcelona, Spain
Search for more papers by this authorÓscar Villacañas
Department de Química Física, Universitat de Barcelona (UB) and the Institut de Recerca en Química Teòrica i Computacional (IQTCUB), Martí i Franquès 1, E-08028 Barcelona, Spain
Search for more papers by this authorCristian Obiol-Pardo
Department de Química Física, Universitat de Barcelona (UB) and the Institut de Recerca en Química Teòrica i Computacional (IQTCUB), Martí i Franquès 1, E-08028 Barcelona, Spain
Search for more papers by this authorMeritxell Antolin-Llovera
Department de Bioquímica i Biología Molecular, Universitat de Barcelona (UB), Avda Diagonal 645, E-08028 Barcelona, Spain
Search for more papers by this authorJaime Rubio-Martinez
Department de Química Física, Universitat de Barcelona (UB) and the Institut de Recerca en Química Teòrica i Computacional (IQTCUB), Martí i Franquès 1, E-08028 Barcelona, Spain
Search for more papers by this authorCorresponding Author
Santiago Imperial
Department de Bioquímica i Biología Molecular, Universitat de Barcelona (UB), Avda Diagonal 645, E-08028 Barcelona, Spain
Department de Bioquímica i Biología Molecular, Universitat de Barcelona (UB), Avda Diagonal 645, E-08028 Barcelona, Spain.Search for more papers by this authorAbstract
The methylerythritol 4-phosphate (MEP) pathway for the biosynthesis of the isoprenoid universal building blocks (isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP)) is present in most of human pathogens and is absent in animals, turning it into a promising therapeutic druggable pathway. Two different strategies, a pharmacophore-directed virtual screening and a protein-protein interaction (PPI)-mimicking cyclic peptide were used to search for compounds that bind to the PPI surface of the 4-(cytidine 5-diphospho)-2C-methyl-D-erythritol kinase (CMK), which catalyzes the fourth step of the MEP pathway. A significant part of the pharmacophore hypothesis used in this study was designed by mimicking water-mediated PPI relevant in the CMK homodimer complex stabilization. After database search and with the aid of docking and molecular dynamics (MD) simulations, a 7H-furo[3,2-g]chromen-7-one derivative and a cyclic peptide were chosen as candidates to be ligands of CMK. Their binding affinities were measured using surface plasmon resonance (SPR) technology. Copyright © 2010 John Wiley & Sons, Ltd.
REFERENCES
- Andreassi JL, 2nd, Leyh TS. 2004. Molecular functions of conserved aspects of the GHMP kinase family. Biochemistry 43(46): 14594–14601.
- Andrews MJ, McInnes C, Kontopidis G, Innes L, Cowan A, Plater A, Fischer PM. 2004. Design, synthesis, biological activity and structural analysis of cyclic peptide inhibitors targeting the substrate recruitment site of cyclin-dependent kinase complexes. Org. Biomol. Chem. 2(19): 2735–2741.
- Bach A, II, Eyermann C, Gross J, Bower M, Harlow R, Weber P, DeGrado W. 1994. Structural studies of a family of high affinity ligands for GPIIb/IIIa. J. Am. Chem. Soc. 116(8): 3207–3219.
- Berendsen H, Postma J, van Gunsteren W, DiNola A, Haak J. 1984. Molecular dynamics with coupling to an external bath. J. Chem. Phys. 81(8): 3684.
- Bonanno JB, Edo C, Eswar N, Pieper U, Romanowski MJ, Ilyin V, Gerchman SE, Kycia H, Studier FW, Sali A, Burley SK. 2001. Structural genomics of enzymes involved in sterol/isoprenoid biosynthesis. Proc. Natl. Acad. Sci. U. S. A. 98(23): 12896–12901.
- Bork P, Sander C, Valencia A. 1993. Convergent evolution of similar enzymatic function on different protein folds: the hexokinase, ribokinase, and galactokinase families of sugar kinases. Protein Sci. 2(1): 31–40.
- Borrmann S, Issifou S, Esser G, Adegnika AA, Ramharter M, Matsiegui PB, Oyakhirome S, Mawili-Mboumba DP, Missinou MA, Kun JF, Jomaa H, Kremsner PG. 2004. Fosmidomycin-clindamycin for the treatment of Plasmodium falciparum malaria. J. Infect. Dis. 190(9): 1534–1540.
- Bradford MM. 1976. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem. 72: 248–254.
- Case DA, Cheatham TE, 3rd, Darden T, Gohlke H, Luo R, Merz KM, Jr, Onufriev A, Simmerling C, Wang B, Woods RJ. 2005. The Amber biomolecular simulation programs. J. Comput. Chem. 26(16): 1668–1688.
- Cochran AG. 2000. Antagonists of protein-protein interactions. Chem. Biol. 7(4): R85–R94.
- Cooper MA. 2002. Optical biosensors in drug discovery. Nat. Rev. Drug. Discov. 1(7): 515–528.
- Chang YP, Chu YH. 2005. Using surface plasmon resonance to directly determine binding affinities of combinatorially selected cyclopeptides and their linear analogs to a streptavidin chip. Anal. Biochem. 340(1): 74–79.
- Darden T, York D, Pedersen L. 1993. Particle mesh Ewald: An N·log(N) method for Ewald sums in large systems. J. Chem. Phys. 98(12): 10089.
- Dathe M, Nikolenko H, Klose J, Bienert M. 2004. Cyclization increases the antimicrobial activity and selectivity of arginine- and tryptophan-containing hexapeptides. Biochemistry 43(28): 9140–9150.
- Dumez E, Snaith JS, Jackson RF, McElroy AB, Overington J, Wythes MJ, Withka JM, McLellan TJ. 2002. Synthesis of macrocyclic, potential protease inhibitors using a generic scaffold. J. Org. Chem. 67(14): 4882–4892.
- Eisenreich W, Schwarz M, Cartayrade A, Arigoni D, Zenk MH, Bacher A. 1998. The deoxyxylulose phosphate pathway of terpenoid biosynthesis in plants and microorganisms. Chem. Biol. 5(9): R221–R233.
- Gabrielsen M, Rohdich F, Eisenreich W, Grawert T, Hecht S, Bacher A, Hunter WN. 2004a. Biosynthesis of isoprenoids: a bifunctional IspDF enzyme from Campylobacter jejuni. Eur. J. Biochem. 271(14): 3028–3035.
- Gabrielsen M, Bond CS, Hallyburton I, Hecht S, Bacher A, Eisenreich W, Rohdich F, Hunter WN. 2004b. Hexameric assembly of the bifunctional methylerythritol 2,4-cyclodiphosphate synthase and protein-protein associations in the deoxy-xylulose-dependent pathway of isoprenoid precursor biosynthesis. J. Biol. Chem. 279(50): 52753–52761.
- Giebel LB, Cass RT, Milligan DL, Young DC, Arze R, Johnson CR. 1995. Screening of cyclic peptide phage libraries identifies ligands that bind streptavidin with high affinities. Biochemistry 34(47): 15430–15435.
- Gimenez-Oya V, Villacanas O, Fernandez-Busquets X, Rubio-Martinez J, Imperial S. 2009. Mimicking direct protein-protein and solvent-mediated interactions in the CDP-methylerythritol kinase homodimer: a pharmacophore-directed virtual screening approach. J. Mol. Model. 15(8): 997–1007.
- Humphrey W, Dalke A, Schulten K. 1996. VMD: visual molecular dynamics. J. Mol. Graph. 14(1): 33–38, 27–28.
- Jakalian A, Jack DB, Bayly CI. 2002. Fast, efficient generation of high-quality atomic charges. AM1-BCC model: II. Parameterization and validation. J. Comput. Chem. 23(16): 1623–1641.
- Johnsson B, Lofas S, Lindquist G. 1991. Immobilization of proteins to a carboxymethyldextran-modified gold surface for biospecific interaction analysis in surface plasmon resonance sensors. Anal. Biochem. 198(2): 268–277.
- Jorgensen W, Chandrasekhar J, Madura J. 1983. Comparison of simple potential functions for simulating liquid water. J. Chem. Phys. 79: 926.
- Kang JH, Kim SY, Lee J, Marquez VE, Lewin NE, Pearce LV, Blumberg PM. 2004. Macrocyclic diacylglycerol-bis-lactones as conformationally constrained analogues of diacylglycerol-lactones. Interactions with protein kinase C. J. Med. Chem. 47(16): 4000–4007.
- Karlsson R. 2004. SPR for molecular interaction analysis: a review of emerging application areas. J. Mol. Recognit. 17(3): 151–161.
- Khan AR, Parrish JC, Fraser ME, Smith WW, Bartlett PA, James MN. 1998. Lowering the entropic barrier for binding conformationally flexible inhibitors to enzymes. Biochemistry 37(48): 16839–16845.
- Kirchmair J, Laggner C, Wolber G, Langer T. 2005. Comparative analysis of protein-bound ligand conformations with respect to catalyst's conformational space subsampling algorithms. J. Chem. Inf. Model. 45(2): 422–430.
- Kollman PA, Massova I, Reyes C, Kuhn B, Huo S, Chong L, Lee M, Lee T, Duan Y, Wang W, Donini O, Cieplak P, Srinivasan J, Case DA, Cheatham TE 3rd. 2000. Calculating structures and free energies of complex molecules: combining molecular mechanics and continuum models. Acc. Chem. Res. 33(12): 889–897.
- Kuzuyama T, Takagi M, Kaneda K, Watanabe H, Dairi T, Seto H. 2000. Studies on the nonmevalonate pathway: conversion of 4-(cytidine 5'diphospho)-2-C-methyl-D-erythritoi to its 2-phospho derivative by 4-(cytidine 5'diphospho)-2-C-methyl-D-erythritoi Kinase. Tetrahedron Lett. 41: 2925–2928.
- Lange BM, Croteau R. 1999. Isopentenyl diphosphate biosynthesis via a mevalonate-independent pathway: isopentenyl monophosphate kinase catalyzes the terminal enzymatic step. Proc. Natl. Acad. Sci. U. S. A. 96(24): 13714–13719.
- Leroux V, Gresh N, Liu W, Garbay C, Maigret B. 2006. Role of water molecules for binding inhibitors in the SH2 domain of Grb2: a molecular dynamics study. Theochem 806(1–3): 51–66.
- Lichtenthaler HK. 1999. The 1-deoxy-D-xylulose-5-phosphate pathway of isoprenoid biosynthesis in plants. Annu. Rev. Plant Physiol. Plant Mol. Biol. 50: 47–65.
- Lüttgen H, Rohdich F, Herz S, Wungsintaweekul J, Hecht S, Schuhr CA, Fellermeier M, Sagner S, Zenk MH, Bacher A, Eisenreich W. 2000. Biosynthesis of terpenoids: YchB protein of Escherichia coli phosphorylates the 2-hydroxy group of 4-diphosphocytidyl-2C-methyl-D-erythritol. Proc. Natl. Acad. Sci. U. S. A. 97(3): 1062–1067.
- Lloyd DG, Garcia-Sosa AT, Alberts IL, Todorov NP, Mancera RL. 2004. The effect of tightly bound water molecules on the structural interpretation of ligand-derived pharmacophore models. J. Comput. Aided. Mol. Des. 18(2): 89–100.
- Marsters JC, Jr, McDowell RS, Reynolds ME, Oare DA, Somers TC, Stanley MS, Rawson TE, Struble ME, Burdick DJ, Chan KS, Duarte CM, Paris KJ, Tom JYK, Wan DT, Xue Y, Bumier JP. 1994. Benzodiazepine peptidomimetic inhibitors of farnesyltransferase. Bioorg. Med. Chem. 2(9): 949–957.
- Miallau L, Alphey MS, Kemp LE, Leonard GA, McSweeney SM, Hecht S, Bacher A, Eisenreich W, Rohdich F, Hunter WN. 2003. Biosynthesis of isoprenoids: crystal structure of 4-diphosphocytidyl-2C-methyl-D-erythritol kinase. Proc. Natl. Acad. Sci. U. S. A. 100(16): 9173–9178.
- Morgan B, Holland D, Brian W. 1994. Structure-based design of an inhibitor of the zinc peptidase thermolysin. J. Am. Chem. Soc. 116(8): 3251–3260.
- Nam NH, Ye G, Sun G, Parang K. 2004. Conformationally constrained peptide analogues of pTyr-Glu-Glu-Ile as inhibitors of the Src SH2 domain binding. J. Med. Chem. 47(12): 3131–3141.
- Obiol-Pardo C, Granadino-Roldan JM, Rubio-Martinez J. 2008. Protein-protein recognition as a first step towards the inhibition of XIAP and Survivin anti-apoptotic proteins. J. Mol. Recognit. 21(3): 190–204.
- Rohdich F, Wungsintaweekul J, Luttgen H, Fischer M, Eisenreich W, Schuhr CA, Fellermeier M, Schramek N, Zenk MH, Bacher A. 2000. Biosynthesis of terpenoids: 4-diphosphocytidyl-2-C-methyl-D-erythritol kinase from tomato. Proc. Natl. Acad. Sci. U. S. A. 97(15): 8251–8256.
- Rohmer M. 1999. The discovery of a mevalonate-independent pathway for isoprenoid biosynthesis in bacteria, algae and higher plants. Nat. Prod. Rep. 16(5): 565–574.
- Ryckaert J, Ciccotti G, Berendsen J. 1977. Numerical integration of the cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes. J. Comput. Phys. 23(3): 327–341.
- Sacchettini JC, Poulter CD. 1997. Creating isoprenoid diversity. Science 277(5333): 1788–1789.
- Samsonov S, Teyra J, Pisabarro MT. 2008. A molecular dynamics approach to study the importance of solvent in protein interactions. Proteins 73(2): 515–525.
-
Spencer RW.
1998.
High-throughput screening of historic collections: observations on file size, biological targets, and file diversity.
Biotechnol. Bioeng.
61(1):
61–67.
10.1002/(SICI)1097-0290(199824)61:1<61::AID-BIT11>3.0.CO;2-C CAS PubMed Web of Science® Google Scholar
- Tsui V, Case DA. 2000. Theory and applications of the generalized born solvation model in macromolecular simulations. Biopolymers 56(4): 275–291.
- Wada T, Kuzuyama T, Satoh S, Kuramitsu S, Yokoyama S, Unzai S, Tame JR, Park SY. 2003. Crystal structure of 4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol kinase, an enzyme in the non-mevalonate pathway of isoprenoid synthesis. J. Biol. Chem. 278(32): 30022–30027.
- Wang J, Wolf RM, Caldwell JW, Kollman PA, Case DA. 2004. Development and testing of a general amber force field. J. Comput. Chem. 25(9): 1157–1174.
- Wang R, Lai L, Wang S. 2002. Further development and validation of empirical scoring functions for structure-based binding affinity prediction. J. Comput. Aided Mol. Des. 16(1): 11–26.
- Weiser J, Shenkin P, Still C. 1999. Approximate atomic surfaces from linear combinations of pairwise overlaps (LCPO). J. Comput. Chem. 20: 217–230.
- Wells JA, McClendon CL. 2007. Reaching for high-hanging fruit in drug discovery at protein-protein interfaces. Nature 450(7172): 1001–1009.
- Zang X, Yu Z, Chu YH. 1998. Tight-binding streptavidin ligands from a cyclic peptide library. Bioorg. Med. Chem. Lett. 8(17): 2327–2332.
- Zobel K, Wang L, Varfolomeev E, Franklin MC, Elliott LO, Wallweber HJ, Okawa DC, Flygare JA, Vucic D, Fairbrother WJ, Deshayes K. 2006. Design, synthesis, and biological activity of a potent Smac mimetic that sensitizes cancer cells to apoptosis by antagonizing IAPs. ACS Chem. Biol. 1(8): 525–533.
