Protein synthesis modulators
View Patent ↗The invention provides a high resolution three-dimensional structure of cycloheximide, either alone or in association with a large ribosomal subunit. The invention provides methods for designing and/or identifying cycloheximide analogs and derivatives that bind and/or modulate the protein biosynthetic activity of the ribosome.
1. A method of identifying a molecule that binds to a large ribosomal subunit, the method comprising the steps of:
(a) providing a molecular model of at least a portion of a cycloheximide binding site of a large subunit of a ribosome created from (i) the atomic co-ordinates for the Haloarcula marismortui large ribosomal subunit found on Disk 1 under file name cycloheximide.pdb, or (ii) atomic co-ordinates derived by homology modeling, molecular replacement, or both homology modeling and molecular replacement using the Haloarcula marismortui atomic co-ordinates found on Disk 1 under file name cycloheximide.pdb, wherein the at least a portion of a cycloheximide binding site is formed by at least 3 amino acid and/or nucleotide residues set forth in Table 1A or Table 1B;
(b) using the molecular model to identify a candidate molecule that binds to at least a portion of the cycloheximide binding site of the molecular model; and
(c) producing the candidate molecule identified in step (b).
2. The method of claim 1 , wherein the molecular model is generated by homology modeling.
3. The method of claim 1 , wherein the molecular model is generated by molecular replacement.
4. The method of claim 1 , wherein the candidate molecule binds specifically to the cycloheximide binding site of the molecular model.
5. The method of claim 1 comprising the additional step of determining whether the candidate molecule modulates ribosomal activity.
6. The method of claim 1 comprising the additional step of identifying a modified candidate molecule.
7. The method of claim 6 comprising the additional step of producing the modified candidate molecule.
8. The method of claim 7 comprising the additional step of determining whether the modified candidate molecule modulates ribosomal activity.
9. The method of claim 8 comprising the additional step of producing and formulating the modified candidate molecule.
10. The method of claim 1 , wherein the molecular model is in an electronic form.
11. The method of claim 1 , wherein the candidate molecule is an antibiotic, an anti-fungal agent, or an anti-cancer agent.
12. The method of claim 1 , wherein the candidate molecule is an antibiotic.
13. The method of claim 1 , wherein the candidate molecule is an anti-fungal agent.
14. The method of claim 1 , wherein the candidate molecule is an anti-cancer agent.