title: The role of water molecules in the structure-based design of (5-hydroxynorvaline)-2-cyclosporin: synthesis, biological activity, and crystallographic analysis with cyclophilin A.
abstract: Analysis of the contact surface of the cyclophilin A (CypA)/cyclosporin A (CsA, 1) crystal structure delineates a unique cavity between both molecules in the vicinity of the Abu-2 side chain atoms of 1 (Abu pocket). Therefore, (5-hydroxynorvaline)-2-cyclosporin (2) was designed and prepared as a CsA derivative which could mediate additional interactions within the pocket. The X-ray crystal structure of the CypA/2 complex at 1.76 A resolution shows that 1 and 2 have identical backbone conformations and that the introduced hydroxypropyl chain makes indeed the expected supplemental interactions with CypA. However, 2 has 8-9-fold lower binding affinity than 1 for CypA. This results from a presumed unfavorable free energy change associated with the displacement of one of the tightly bound water molecules within the pocket and a change in prebinding equilibria. The role of the later was assessed by comparing the conformation distribution of 1 and 2 to that of norvaline-2-cyclosporin (3) and norvaline-2-(D-MeSer)-3-cyclosporin (4).
authors.affiliation: Sandoz Pharma Ltd., Preclinical Research, Basel, Switzerland.
authors.forename: V
authors.initials: V
authors.lastname: Mikol
authors.forename: C
authors.initials: C
authors.lastname: Papageorgiou
authors.forename: X
authors.initials: X
authors.lastname: Borer
mesh_terms: D000591:Amino Acid Isomerases / Q000737:chemistry*; D000595:Amino Acid Sequence; D002352:Carrier Proteins / Q000737:chemistry*; D018360:Crystallography, X-Ray; D016572:Cyclosporine / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D007166:Immunosuppressive Agents / Q000737:chemistry* / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D019696:Peptidylprolyl Isomerase; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014867:Water / Q000737:chemistry*
chemical_list: C095357:(5-hydroxynorvaline)-2-cyclosporin; D002352:Carrier Proteins; D007166:Immunosuppressive Agents; D014867:Water; D016572:Cyclosporine; D000591:Amino Acid Isomerases; D019696:Peptidylprolyl Isomerase