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Conformational polymorphism in peptidic and nonpeptidic drug molecules
1Structural Biochemistry Group, Department of Biochemistry, The University of Edinburgh, UK.
Biopolymers
|January 1, 1996
Summary
Macrolide and cyclosporin ligands undergo significant conformational changes upon binding to their protein targets. A novel cyclosporin-like ligand (SDZ214-103) exhibits distinct free and bound conformations, offering new insights into ligand-protein interactions.
Area of Science:
- Biochemistry
- Structural Biology
- Pharmacology
Background:
- Macrolide and cyclosporin ligands, despite chemical differences, share structural and biological properties.
- Ligand conformation drastically changes between free and bound states, impacting molecular surface interactions.
Purpose of the Study:
- To elucidate the three-dimensional structure of a novel cyclosporin-like ligand, SDZ214-103.
- To compare the conformations of SDZ214-103 in its free state and when bound to cyclophilin.
Main Methods:
- X-ray crystallography was employed to determine the structure of SDZ214-103.
- Structural analysis was performed on both the free ligand and its complex with cyclophilin.
Main Results:
- SDZ214-103 displays a unique conformation in its free crystalline state, differing from cyclosporin A.
- When bound to cyclophilin, SDZ214-103 adopts a conformation highly similar to that of cyclosporin A.
- Conformational changes involve cis-trans isomerization around amide bonds, altering hydrogen-bonding capabilities.
Conclusions:
- Novel cyclosporin-like ligands can exhibit distinct conformational behaviors compared to established analogs.
- Understanding these ligand-protein conformational dynamics is crucial for drug design and development targeting FK506 binding proteins and cyclophilins.