Generation and evaluation of putative neuroregenerative drugs. Part 1 : Virtual point mutations to the polyketide rapamycin

• Published in: Bioorganic & medicinal chemistry Vol. 8; no. 3; pp. 617 - 624
• Main Authors: ADALSTEINSSON, H, BRUICE, T. C
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Science 01.03.2000
• Subjects: Anti-Bacterial Agents - metabolism; Binding Sites; Biological and medical sciences; Computer Simulation; Genetic Engineering; Immunophilins - metabolism; Immunosuppressive Agents - metabolism; Ligands; Medical sciences; Miscellaneous; Models, Molecular; Molecular Structure; Multienzyme Complexes - metabolism; Nerve Regeneration - drug effects; Neuropharmacology; Pharmacology. Drug treatments; Point Mutation; Sirolimus - analogs & derivatives; Sirolimus - metabolism; Solvents; Tacrolimus - metabolism; Tacrolimus Binding Proteins; Thermodynamics; Neurite; Sirolimus; Ligand; Lactam; Molecular interaction; Nervous system; Binding site; Modeling; Macrocycle; Nerve; Binding protein; Isomerases; Structure activity relation; Molecular model; cis-trans-Isomerases; Oxygen nitrogen heterocycle; Peptidylprolyl isomerase; Enzyme; Lactone; Macrolide; Regeneration; Biological fixation; Chemical modification; Polyketides; Binding energy; Immunosuppressive agent
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/S0968-0896(99)00323-5

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.