Ligand development using PDE4B crystal structures
First Claim
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1. A method for developing ligands binding to PDE4B, comprising identifying as molecular scaffolds one or more compounds that bind to a binding site of PDE4B;
- determining the orientation of at least one molecular scaffold in co-crystals with PDE4B; and
identifying chemical structures of said molecular scaffolds, that, when modified, alter the binding affinity or binding specificity or both between the molecular scaffold and PDE4B; and
synthesizing a ligand wherein one or more of the chemical structures of the molecular scaffold is modified to provide a ligand that binds to PDE4B with altered binding affinity or binding specificity or both.
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Abstract
The use of PDE4B crystals and strucural information for identifying molecular scaffolds and for developing ligands that bind to and modulate PDE4B is described.
115 Citations
50 Claims
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1. A method for developing ligands binding to PDE4B, comprising
identifying as molecular scaffolds one or more compounds that bind to a binding site of PDE4B; -
determining the orientation of at least one molecular scaffold in co-crystals with PDE4B; and
identifying chemical structures of said molecular scaffolds, that, when modified, alter the binding affinity or binding specificity or both between the molecular scaffold and PDE4B; and
synthesizing a ligand wherein one or more of the chemical structures of the molecular scaffold is modified to provide a ligand that binds to PDE4B with altered binding affinity or binding specificity or both. - View Dependent Claims (2, 3, 4, 5, 6)
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7. A method for developing ligands specific for PDE4B, comprising
identifying a compound that binds to a plurality of phosphodiesterases; - and
determining whether a derivative of said compound has greater specificity for PDE4B than said compound. - View Dependent Claims (8, 9, 10, 11, 12, 13, 14, 15)
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- 16. A co-crystal of PDE4B and a PDE4B binding compound, wherein said binding compound includes a structural core selected from the group consisting of Scaffold core I, Scaffold core II, and Scaffold core III.
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18. A crystalline form of PDE4B phosphodiesterase domain, having coordinates as described in Table 1.
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19. A method for obtaining a crystal of PDE4B, comprising subjecting PDE4B protein at 5-20 mg/ml to crystallization condition substantially equivalent to 30% PEG 400, 0.2M MgCl2, 0.1M Tris pH 8.5, 1 mM binding compound, at 4°
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or 20% PEG 3000, 0.2M Ca(OAc)2, 0.1M Tris pH 7.0, 1 mM binding compound, 15.9 mg/ml protein at 4°
C.;
or 1.8M-2.0M ammonium sulphate, 0.1 M CAPS pH 10.0-10.5, 0.2M Lithium sulphate. - View Dependent Claims (20)
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- 21. An electronic representation of a crystal structure of PDE4B, containing atomic coordinate representations corresponding to the coordinates listed in Table 1.
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25. A method for developing a biological agent, comprising
analyzing a PDE4B crystal structure and identifying at least one sub-structure for forming a said biological agent.
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31. A method for attaching a PDE4B binding compound to an attachment component, comprising
identifying energetically allowed sites for attachment of a said attachment component on a phosphodiesterase binding compound; - and
attaching said compound or derivative thereof to said attachment component at said energetically allowed site. - View Dependent Claims (32, 33, 34, 35, 36, 37, 38)
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39. A modified compound, comprising
a PDE4B binding compound, with a linker moiety attached thereto at an energetically allowed site for binding of said modified compound to PDE4B.
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43. A method for identifying a compound having selectivity between PDE4B and PDE4D, comprising
analyzing whether a compound differentially interacts in PDE4B and PDE4D in at least one of PDE4B/4D selectivity sites 1, 2, and 3, wherein a differential interaction is indicative of said selectivity.
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48. A method for treating a subject for a PDE4B related disease or condition, comprising
administering to said subject a compound comprising a structural core selected from the group consisting of Scaffold core I, Scaffold core II, and Scaffold core III.
Specification