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Simultaneous targeting of MyD88 and Nur77 as an effective approach for the treatment of inflammatory diseases.

Uzma S, Baig MS - Drug Des Devel Ther (2016)

Bottom Line: Myeloid differentiation primary response protein 88 (MyD88) has long been considered a central player in the inflammatory pathway.In this study, we have designed inhibitors that can inhibit both MyD88 and Nur77 at the same time.To perform this, we developed a homodimeric model of MyD88 and, along with the crystal structure of Nur77, screened a virtual library of compounds from the traditional Chinese medicine database containing ~61,000 compounds.

View Article: PubMed Central - PubMed

Affiliation: Divsion of Chemistry, School of Basic Sciences, Indore, MP, India.

ABSTRACT
Myeloid differentiation primary response protein 88 (MyD88) has long been considered a central player in the inflammatory pathway. Recent studies clearly suggest that it is an important therapeutic target in inflammation. On the other hand, a recent study on the interaction between the orphan nuclear receptor (Nur77) and p38α, leading to increased lipopolysaccharide-induced hyperinflammatory response, suggests this binary complex as a therapeutic target. In this study, we have designed inhibitors that can inhibit both MyD88 and Nur77 at the same time. Since both MyD88 and Nur77 are an integral part of the pathways involving lipopolysaccharide-induced activation of NF-κB-mediated inflammation, we tried to target both proteins with the same library in order to retrieve compounds having dual inhibitory properties. To perform this, we developed a homodimeric model of MyD88 and, along with the crystal structure of Nur77, screened a virtual library of compounds from the traditional Chinese medicine database containing ~61,000 compounds. We analyzed the resulting hits for their efficacy for dual binding and probed them for developing a common pharmacophore model that could be used as a prototype to screen compound libraries as well as to guide combinatorial library design to search for ideal dual-target inhibitors. Thus, our study explores the identification of novel leads having dual inhibiting effects due to binding to both MyD88 and Nur77 targets.

No MeSH data available.


Related in: MedlinePlus

Superimposed structures of the docked MyD88 dimers showing complete overlap of the docked complexes.Notes: (A) The ClusPro docked complex is depicted in pink ribbons, while the GRAMM-X docked complex is shown in green ribbons. (B) Zoomed interfaces of the complexes showing the position of BB-loop residues in ball and stick.Abbreviation: GRAMM-X, Global Range Molecular Matching.
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f2-dddt-10-1557: Superimposed structures of the docked MyD88 dimers showing complete overlap of the docked complexes.Notes: (A) The ClusPro docked complex is depicted in pink ribbons, while the GRAMM-X docked complex is shown in green ribbons. (B) Zoomed interfaces of the complexes showing the position of BB-loop residues in ball and stick.Abbreviation: GRAMM-X, Global Range Molecular Matching.

Mentions: The MyD88 monomeric protein structure is already available in the Protein Data Bank (PDB).21 However, the dimeric structure is unavailable. Recently, Olson et al18 published a homology modeled structure of the dimeric protein. We similarly modeled the dimer structure utilizing the crystal structures of monomeric MyD88 structures using two different programs: Global Range Molecular Matching (GRAMM-X) and Clustpro. When we compared the top docked poses of both the servers, we observed that they were almost superimposable (Figure 2A). Our models were very similar to that of Olson et al, specifically in terms of the highly conserved BB-loop position. As in their model, the BB-loop residues form an integral part of the dimeric interface of the structure; similarly, our top-docked conformations from both the servers also had the BB loop at the dimer interface (Figure 2B). The BB loop has residues ranging from 196 to 202 comprising the fairly conserved (25%–75%) sequence motif VLPG, with nearly invariant proline and glycine residues.22 The BB-loop region is a long coil region with flexible conformations, which could be attributed to its positioning at the interface where much action has been going on in terms of activation by dimerization and inactivation by monomerization due to various signaling events.


Simultaneous targeting of MyD88 and Nur77 as an effective approach for the treatment of inflammatory diseases.

Uzma S, Baig MS - Drug Des Devel Ther (2016)

Superimposed structures of the docked MyD88 dimers showing complete overlap of the docked complexes.Notes: (A) The ClusPro docked complex is depicted in pink ribbons, while the GRAMM-X docked complex is shown in green ribbons. (B) Zoomed interfaces of the complexes showing the position of BB-loop residues in ball and stick.Abbreviation: GRAMM-X, Global Range Molecular Matching.
© Copyright Policy
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4862341&req=5

f2-dddt-10-1557: Superimposed structures of the docked MyD88 dimers showing complete overlap of the docked complexes.Notes: (A) The ClusPro docked complex is depicted in pink ribbons, while the GRAMM-X docked complex is shown in green ribbons. (B) Zoomed interfaces of the complexes showing the position of BB-loop residues in ball and stick.Abbreviation: GRAMM-X, Global Range Molecular Matching.
Mentions: The MyD88 monomeric protein structure is already available in the Protein Data Bank (PDB).21 However, the dimeric structure is unavailable. Recently, Olson et al18 published a homology modeled structure of the dimeric protein. We similarly modeled the dimer structure utilizing the crystal structures of monomeric MyD88 structures using two different programs: Global Range Molecular Matching (GRAMM-X) and Clustpro. When we compared the top docked poses of both the servers, we observed that they were almost superimposable (Figure 2A). Our models were very similar to that of Olson et al, specifically in terms of the highly conserved BB-loop position. As in their model, the BB-loop residues form an integral part of the dimeric interface of the structure; similarly, our top-docked conformations from both the servers also had the BB loop at the dimer interface (Figure 2B). The BB loop has residues ranging from 196 to 202 comprising the fairly conserved (25%–75%) sequence motif VLPG, with nearly invariant proline and glycine residues.22 The BB-loop region is a long coil region with flexible conformations, which could be attributed to its positioning at the interface where much action has been going on in terms of activation by dimerization and inactivation by monomerization due to various signaling events.

Bottom Line: Myeloid differentiation primary response protein 88 (MyD88) has long been considered a central player in the inflammatory pathway.In this study, we have designed inhibitors that can inhibit both MyD88 and Nur77 at the same time.To perform this, we developed a homodimeric model of MyD88 and, along with the crystal structure of Nur77, screened a virtual library of compounds from the traditional Chinese medicine database containing ~61,000 compounds.

View Article: PubMed Central - PubMed

Affiliation: Divsion of Chemistry, School of Basic Sciences, Indore, MP, India.

ABSTRACT
Myeloid differentiation primary response protein 88 (MyD88) has long been considered a central player in the inflammatory pathway. Recent studies clearly suggest that it is an important therapeutic target in inflammation. On the other hand, a recent study on the interaction between the orphan nuclear receptor (Nur77) and p38α, leading to increased lipopolysaccharide-induced hyperinflammatory response, suggests this binary complex as a therapeutic target. In this study, we have designed inhibitors that can inhibit both MyD88 and Nur77 at the same time. Since both MyD88 and Nur77 are an integral part of the pathways involving lipopolysaccharide-induced activation of NF-κB-mediated inflammation, we tried to target both proteins with the same library in order to retrieve compounds having dual inhibitory properties. To perform this, we developed a homodimeric model of MyD88 and, along with the crystal structure of Nur77, screened a virtual library of compounds from the traditional Chinese medicine database containing ~61,000 compounds. We analyzed the resulting hits for their efficacy for dual binding and probed them for developing a common pharmacophore model that could be used as a prototype to screen compound libraries as well as to guide combinatorial library design to search for ideal dual-target inhibitors. Thus, our study explores the identification of novel leads having dual inhibiting effects due to binding to both MyD88 and Nur77 targets.

No MeSH data available.


Related in: MedlinePlus