title: Generation and evaluation of putative neuroregenerative drugs. Part 2: screening virtual libraries of novel polyketides which possess the binding domain of rapamycin.
abstract: The use of computational methods to direct engineered biosynthesis toward candidates based on the desired properties of the target compounds has been explored. The objective for this study has been the modification of rapamycin in order to eliminate its immunosuppressive activity and retain its neuroregenerative abilities. We have designed analogues of rapamycin which have truncated effector domains but retain the ability to bind to FKBP proteins, which is a prerequisite for the neuroregenerative abilities of the drugs. The procedures described here consist of the screening of large virtual libraries of molecules which retain the binding domain of rapamycin but in which different substitute ketide units replace the effector domain. These methods have provided analogues of rapamycin that cannot retain the immunosuppressive abilities of rapamycin, have a binding affinity to FKBP12 identical to that of rapamycin (by linear interaction energy calculations), and are suitable for synthesis by modified polyketide synthases.
authors.affiliation: Department of Chemistry, University of California, Santa Barbara 93106, USA.
authors.forename: H
authors.initials: H
authors.lastname: Adalsteinsson
authors.forename: T C
authors.initials: TC
authors.lastname: Bruice
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry; D001665:Binding Sites; D003198:Computer Simulation; D006801:Humans; D020104:Immunophilins / Q000737:chemistry / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000378:metabolism; D007231:Infant, Newborn; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D009416:Nerve Regeneration / Q000187:drug effects*; D011485:Protein Binding; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000378:metabolism*; D012997:Solvents; D022021:Tacrolimus Binding Proteins; D013816:Thermodynamics; D014584:User-Computer Interface
chemical_list: D000900:Anti-Bacterial Agents; D007166:Immunosuppressive Agents; D008024:Ligands; D012997:Solvents; D022021:Tacrolimus Binding Proteins; D020104:Immunophilins; D020123:Sirolimus