title: Dictyostatin flexibility bridges conformations in solution and in the β-tubulin taxane binding site.
abstract: Dictyostatin (DCT, 1) is a complex, flexible polyketide macrolide that demonstrates potent microtubule-polymerization activity. Both a solution structure (2a) and a possible binding mode for DCT (Conf-1) have been proposed by earlier NMR experiments. In the present study, the conformational landscape of DCT in DMSO-d(6) and methanol-d(4) was explored using extensive force-field-based conformational searches combined with geometric parameters derived from solution NMR data. The results portray a diversity of conformations for dictyostatin that illustrates the molecule's flexibility and excludes the previously suggested dominant solution conformation 2a. One conformation present in DMSO-d(6) with a 7% population (Conf-2, 0.6 kcal/mol above the global minimum at 298°) also satisfies the TR-NOESY NMR parameters of Canales et al. that characterize the taxane binding-site interaction between DCT and assembled microtubules in water. Application of several docking methods (Glide, Autodock, and RosettaLigand) has identified a low-energy binding model of the DCT/β-tubulin complex (Pose-2/Conf-2) that is gratifyingly compatible with the emerging DCT structure-activity data.
authors.affiliation: Department of Chemistry, Emory University, Atlanta, Georgia 30322, USA.
authors.forename: Ashutosh S
authors.initials: AS
authors.lastname: Jogalekar
authors.forename: Krishnan
authors.initials: K
authors.lastname: Damodaran
authors.forename: Frederik H
authors.initials: FH
authors.lastname: Kriel
authors.forename: Won-Hyuk
authors.initials: WH
authors.lastname: Jung
authors.forename: Ana A
authors.initials: AA
authors.lastname: Alcaraz
authors.forename: Shi
authors.initials: S
authors.lastname: Zhong
authors.forename: Dennis P
authors.initials: DP
authors.lastname: Curran
authors.forename: James P
authors.initials: JP
authors.lastname: Snyder
mesh_terms: D001665:Binding Sites; D001952:Bridged-Ring Compounds / Q000737:chemistry*; D018942:Macrolides / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D012996:Solutions; D014404:Tubulin / Q000737:chemistry*
chemical_list: D001952:Bridged-Ring Compounds; D018942:Macrolides; D012996:Solutions; D014404:Tubulin; C470814:dictyostatin