Computational Design of Inhibitory Agents of BMP-Noggin Interaction to Promote Osteogenesis
Bone growth factors, such as Bone Morphogenic
Protein-2 (BMP-2) have been approved by the FDA to replace grafting for some surgical interventions, but the high dose requirement limits its use in patients. Noggin, an extracellular protein, blocks the effect of BMP-2 by binding to BMP. Preventing
the BMP-2/noggin interaction will help increase the free
concentration of BMP-2 and therefore should enhance its efficacy to
induce bone formation. The work presented here involves
computational design of novel small molecule inhibitory agents of BMP-2/noggin interaction, based on our current understanding of
BMP-2, and its known putative ligands (receptors and antagonists). A
successful acquisition of such an inhibitory agent of BMP-2/noggin interaction would allow clinicians to reduce the dose required of
BMP-2 protein in clinical applications to promote osteogenesis. The
available crystal structures of the BMPs, its receptors, and the binding partner noggin were analyzed to identify the critical residues
involved in their interaction. In presenting this study, LUDI de novo design method was utilized to perform virtual screening of a large
number of compounds from a commercially available library against the binding sites of noggin to identify the lead chemical compounds
that could potentially block BMP-noggin interaction with a high specificity.
[1] Lin SJ, Lerch TF, Cook RW, Jardetzky TS, Woodruff TK: The structural
basis of TGF-beta, bone morphogenetic protein, and activin ligand binding. Reproduction 2006, 132(2):179-190.
[2] Mace PD, Cutfield JF, Cutfield SM: High resolution structures of the
bone morphogenetic protein type II receptor in two crystal forms:
implications for ligand binding. Biochem Biophys Res Commun 2006,
351(4):831-838.
[3] Gazzerro E, Minetti C: Potential drug targets within bone morphogenetic
protein signaling pathways. Curr Opin Pharmacol 2007, 7(3):325-333.
[4] Kuo PL, Huang YT, Chang CH, Chang JK: Bone morphogenetic
protein-2 and -4 (BMP-2 and -4) mediates fraxetin-induced maturation and differentiation in human osteoblast-like cell lines. Biol Pharm Bull
2006, 29(1):119-124.
[5] Rosen V, Cox K, Hattersley G: Bone morphogenetic proteins. In
Principles of Bone Biology 1996: 661-671.
[6] Wozney JM. Bone morphogenetic proteins and their gene expression. In
Cellular and molecular biology of bone 1993:131-167.
[7] Sebald W, Nickel J, Zhang JL, Mueller TD: Molecular recognition in
bone morphogenetic protein (BMP)/receptor interaction. Biol Chem
2004, 385(8):697-710.
[8] Rosen V: BMP and BMP inhibitors in bone. Ann N Y Acad Sci 2006, 1068:19-25.
[9] Lin Y, Martin J, Gruendler C, Farley J, Meng X, Li BY, Lechleider R, Huff C, Kim RH, Grasser WA et al: A novel link between the proteasome pathway and the signal transduction pathway of the bone morphogenetic proteins (BMPs). BMC Cell Biol 2002, 3:15.
[10] Larrain J, Bachiller D, Lu B, Agius E, Piccolo S, De Robertis EM:
BMP-binding modules in chordin: a model for signalling regulation in the extracellular space. Development 2000, 127(4):821-830.
[11] Zimmerman LB, De Jesus-Escobar JM, Harland RM: The Spemann
organizer signal noggin binds and inactivates bone morphogenetic
protein 4. Cell 1996, 86(4):599-606.
[12] Valenzuela DM, Economides AN, Rojas E, Lamb TM, Nunez L, Jones
P, Lp NY, Espinosa R, 3rd, Brannan CI, Gilbert DJ et al: Identification
of mammalian noggin and its expression in the adult nervous system. J
Neurosci 1995, 15(9):6077-6084.
[13] Re'em-Kalma Y, Lamb T, Frank D: Competition between noggin and
bone morphogenetic protein 4 activities may regulate dorsalization
during Xenopus development. Proc Natl Acad Sci U S A 1995,
92(26):12141-12145.
[14] Wu XB, Li Y, Schneider A, Yu W, Rajendren G, Iqbal J, Yamamoto M,
Alam M, Brunet LJ, Blair HC et al: Impaired osteoblastic
differentiation, reduced bone formation, and severe osteoporosis in
noggin-overexpressing mice. J Clin Invest 2003, 112(6):924-934.
[15] Groppe J, Greenwald J, Wiater E, Rodriguez-Leon J, Economides AN,
Kwiatkowski W, Affolter M, Vale WW, Belmonte JC, Choe S: Structural basis of BMP signalling inhibition by the cystine knot protein
Noggin. Nature 2002, 420(6916):636-642.
[16] Groppe J, Greenwald J, Wiater E, Rodriguez-Leon J, Economides AN,
Kwiatkowski W, Baban K, Affolter M, Vale WW, Belmonte JC et al:
Structural basis of BMP signaling inhibition by Noggin, a novel twelvemembered
cystine knot protein. J Bone Joint Surg Am 2003, 85-A Suppl 3:52-58.
[17] Gasteiger E, Jung E, Bairoch A: SWISS-PROT: connecting
biomolecular knowledge via a protein database. Curr Issues Mol Biol 2001, 3(3):47-55.
[18] Apweiler R, Bairoch A, Wu CH, Barker WC, Boeckmann B, Ferro S,
Gasteiger E, Huang H, Lopez R, Magrane M et al: UniProt: the Universal Protein knowledgebase. Nucleic Acids Res 2004, 32(Database
issue):D115-119.
[19] Bairoch A, Apweiler R, Wu CH, Barker WC, Boeckmann B, Ferro S,
Gasteiger E, Huang H, Lopez R, Magrane M et al: The Universal
Protein Resource (UniProt). Nucleic Acids Res 2005, 33(Database issue):D154-159.
[20] Wu CH, Apweiler R, Bairoch A, Natale DA, Barker WC, Boeckmann B,
Ferro S, Gasteiger E, Huang H, Lopez R et al: The Universal Protein
Resource (UniProt): an expanding universe of protein information.
Nucleic Acids Res 2006, 34(Database issue):D187-191.
[21] Thompson JD, Higgins DG, Gibson TJ: CLUSTAL W: improving the
sensitivity of progressive multiple sequence alignment through sequence
weighting, position-specific gap penalties and weight matrix choice.
Nucleic Acids Res 1994, 22(22):4673-4680.
[22] Richmond TJ, Richards FM: Packing of a-helices: geometric
constraints, and contact areas. J Mol Biol 1978, 119:537-555.
[23] Sayle RA, Milner-White EJ: RASMOL: biomolecular graphics for all.
Trends Biochem Sci 1995, 20(9):374.
[24] Bernstein HJ: Recent changes to RasMol, recombining the variants.
Trends Biochem Sci 2000, 25(9):453-455.
[25] Maiti R, Van Domselaar GH, Zhang H, Wishart DS: SuperPose: a
simple server for sophisticated structural superposition. Nucleic Acids
Res 2004, 32(Web Server issue):W590-594.
[26] Bohm HJ: The computer program LUDI: a new method for the de novo
design of enzyme inhibitors. J Comput Aided Mol Des 1992, 6(1):61-78.
[27] Bohm HJ: On the use of LUDI to search the Fine Chemicals Directory
for ligands of proteins of known three-dimensional structure. J Comput
Aided Mol Des 1994, 8(5):623-632.
[1] Lin SJ, Lerch TF, Cook RW, Jardetzky TS, Woodruff TK: The structural
basis of TGF-beta, bone morphogenetic protein, and activin ligand binding. Reproduction 2006, 132(2):179-190.
[2] Mace PD, Cutfield JF, Cutfield SM: High resolution structures of the
bone morphogenetic protein type II receptor in two crystal forms:
implications for ligand binding. Biochem Biophys Res Commun 2006,
351(4):831-838.
[3] Gazzerro E, Minetti C: Potential drug targets within bone morphogenetic
protein signaling pathways. Curr Opin Pharmacol 2007, 7(3):325-333.
[4] Kuo PL, Huang YT, Chang CH, Chang JK: Bone morphogenetic
protein-2 and -4 (BMP-2 and -4) mediates fraxetin-induced maturation and differentiation in human osteoblast-like cell lines. Biol Pharm Bull
2006, 29(1):119-124.
[5] Rosen V, Cox K, Hattersley G: Bone morphogenetic proteins. In
Principles of Bone Biology 1996: 661-671.
[6] Wozney JM. Bone morphogenetic proteins and their gene expression. In
Cellular and molecular biology of bone 1993:131-167.
[7] Sebald W, Nickel J, Zhang JL, Mueller TD: Molecular recognition in
bone morphogenetic protein (BMP)/receptor interaction. Biol Chem
2004, 385(8):697-710.
[8] Rosen V: BMP and BMP inhibitors in bone. Ann N Y Acad Sci 2006, 1068:19-25.
[9] Lin Y, Martin J, Gruendler C, Farley J, Meng X, Li BY, Lechleider R, Huff C, Kim RH, Grasser WA et al: A novel link between the proteasome pathway and the signal transduction pathway of the bone morphogenetic proteins (BMPs). BMC Cell Biol 2002, 3:15.
[10] Larrain J, Bachiller D, Lu B, Agius E, Piccolo S, De Robertis EM:
BMP-binding modules in chordin: a model for signalling regulation in the extracellular space. Development 2000, 127(4):821-830.
[11] Zimmerman LB, De Jesus-Escobar JM, Harland RM: The Spemann
organizer signal noggin binds and inactivates bone morphogenetic
protein 4. Cell 1996, 86(4):599-606.
[12] Valenzuela DM, Economides AN, Rojas E, Lamb TM, Nunez L, Jones
P, Lp NY, Espinosa R, 3rd, Brannan CI, Gilbert DJ et al: Identification
of mammalian noggin and its expression in the adult nervous system. J
Neurosci 1995, 15(9):6077-6084.
[13] Re'em-Kalma Y, Lamb T, Frank D: Competition between noggin and
bone morphogenetic protein 4 activities may regulate dorsalization
during Xenopus development. Proc Natl Acad Sci U S A 1995,
92(26):12141-12145.
[14] Wu XB, Li Y, Schneider A, Yu W, Rajendren G, Iqbal J, Yamamoto M,
Alam M, Brunet LJ, Blair HC et al: Impaired osteoblastic
differentiation, reduced bone formation, and severe osteoporosis in
noggin-overexpressing mice. J Clin Invest 2003, 112(6):924-934.
[15] Groppe J, Greenwald J, Wiater E, Rodriguez-Leon J, Economides AN,
Kwiatkowski W, Affolter M, Vale WW, Belmonte JC, Choe S: Structural basis of BMP signalling inhibition by the cystine knot protein
Noggin. Nature 2002, 420(6916):636-642.
[16] Groppe J, Greenwald J, Wiater E, Rodriguez-Leon J, Economides AN,
Kwiatkowski W, Baban K, Affolter M, Vale WW, Belmonte JC et al:
Structural basis of BMP signaling inhibition by Noggin, a novel twelvemembered
cystine knot protein. J Bone Joint Surg Am 2003, 85-A Suppl 3:52-58.
[17] Gasteiger E, Jung E, Bairoch A: SWISS-PROT: connecting
biomolecular knowledge via a protein database. Curr Issues Mol Biol 2001, 3(3):47-55.
[18] Apweiler R, Bairoch A, Wu CH, Barker WC, Boeckmann B, Ferro S,
Gasteiger E, Huang H, Lopez R, Magrane M et al: UniProt: the Universal Protein knowledgebase. Nucleic Acids Res 2004, 32(Database
issue):D115-119.
[19] Bairoch A, Apweiler R, Wu CH, Barker WC, Boeckmann B, Ferro S,
Gasteiger E, Huang H, Lopez R, Magrane M et al: The Universal
Protein Resource (UniProt). Nucleic Acids Res 2005, 33(Database issue):D154-159.
[20] Wu CH, Apweiler R, Bairoch A, Natale DA, Barker WC, Boeckmann B,
Ferro S, Gasteiger E, Huang H, Lopez R et al: The Universal Protein
Resource (UniProt): an expanding universe of protein information.
Nucleic Acids Res 2006, 34(Database issue):D187-191.
[21] Thompson JD, Higgins DG, Gibson TJ: CLUSTAL W: improving the
sensitivity of progressive multiple sequence alignment through sequence
weighting, position-specific gap penalties and weight matrix choice.
Nucleic Acids Res 1994, 22(22):4673-4680.
[22] Richmond TJ, Richards FM: Packing of a-helices: geometric
constraints, and contact areas. J Mol Biol 1978, 119:537-555.
[23] Sayle RA, Milner-White EJ: RASMOL: biomolecular graphics for all.
Trends Biochem Sci 1995, 20(9):374.
[24] Bernstein HJ: Recent changes to RasMol, recombining the variants.
Trends Biochem Sci 2000, 25(9):453-455.
[25] Maiti R, Van Domselaar GH, Zhang H, Wishart DS: SuperPose: a
simple server for sophisticated structural superposition. Nucleic Acids
Res 2004, 32(Web Server issue):W590-594.
[26] Bohm HJ: The computer program LUDI: a new method for the de novo
design of enzyme inhibitors. J Comput Aided Mol Des 1992, 6(1):61-78.
[27] Bohm HJ: On the use of LUDI to search the Fine Chemicals Directory
for ligands of proteins of known three-dimensional structure. J Comput
Aided Mol Des 1994, 8(5):623-632.
@article{"International Journal of Medical, Medicine and Health Sciences:50802", author = "Shaila Ahmed and Raghu Prasad Rao Metpally and Sreedhara Sangadala and Boojala Vijay B Reddy", title = "Computational Design of Inhibitory Agents of BMP-Noggin Interaction to Promote Osteogenesis", abstract = "Bone growth factors, such as Bone Morphogenic
Protein-2 (BMP-2) have been approved by the FDA to replace grafting for some surgical interventions, but the high dose requirement limits its use in patients. Noggin, an extracellular protein, blocks the effect of BMP-2 by binding to BMP. Preventing
the BMP-2/noggin interaction will help increase the free
concentration of BMP-2 and therefore should enhance its efficacy to
induce bone formation. The work presented here involves
computational design of novel small molecule inhibitory agents of BMP-2/noggin interaction, based on our current understanding of
BMP-2, and its known putative ligands (receptors and antagonists). A
successful acquisition of such an inhibitory agent of BMP-2/noggin interaction would allow clinicians to reduce the dose required of
BMP-2 protein in clinical applications to promote osteogenesis. The
available crystal structures of the BMPs, its receptors, and the binding partner noggin were analyzed to identify the critical residues
involved in their interaction. In presenting this study, LUDI de novo design method was utilized to perform virtual screening of a large
number of compounds from a commercially available library against the binding sites of noggin to identify the lead chemical compounds
that could potentially block BMP-noggin interaction with a high specificity.", keywords = "Transforming growth factor-beta, Bone morphogenic proteins, Noggin, LUDI de novo design method, CAP small molecules.", volume = "3", number = "10", pages = "281-5", }
