title: Generation and evaluation of putative neuroregenerative drugs. Part 1: virtual point mutations to the polyketide rapamycin.
abstract: This paper explores the use of computational methods to direct engineered biosynthesis based on the desired properties of the target compounds. The immunosuppressive properties of rapamycin are a result of the formation of the complex FKBP12-rapamycin-FRAP. Neuroregenerative properties are exhibited by the complex or complexes of rapamycin with FKBP proteins. Our objective has been to design biosynthetically available analogues of rapamycin that bind tightly to FKBP12 but not to FRAP. This has been carried out by successive single ketide deletions from the effector domain of rapamycin. The approach described here has yielded modified rapamycin analogues (RP2 and RP3) as targets for biosynthesis by modified polyketide synthases. RP2 and RP3 have an identical binding affinity (linear interaction energy calculation) to FKBP12 as rapamycin but little or no affinity for binding to FRAP.
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 / Q000378:metabolism; D001665:Binding Sites; D003198:Computer Simulation; D005818:Genetic Engineering; D020104:Immunophilins / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D009097:Multienzyme Complexes / Q000378:metabolism; D009416:Nerve Regeneration / Q000187:drug effects*; D017354:Point Mutation; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000378:metabolism*; D012997:Solvents; D016559:Tacrolimus / Q000378:metabolism; D022021:Tacrolimus Binding Proteins; D013816:Thermodynamics
chemical_list: D000900:Anti-Bacterial Agents; D007166:Immunosuppressive Agents; D008024:Ligands; D009097:Multienzyme Complexes; D012997:Solvents; D022021:Tacrolimus Binding Proteins; D020104:Immunophilins; D020123:Sirolimus; D016559:Tacrolimus