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Ultrapotent vinblastines in which added molecular complexity further disrupts the target tubulin dimer-dimer interface.

ABSTRACT: Approaches to improving the biological properties of natural products typically strive to modify their structures to identify the essential pharmacophore, or make functional group changes to improve biological target affinity or functional activity, change physical properties, enhance stability, or introduce conformational constraints. Aside from accessible semisynthetic modifications of existing functional groups, rarely does one consider using chemical synthesis to add molecular complexity to the natural product. In part, this may be attributed to the added challenge intrinsic in the synthesis of an even more complex compound. Herein, we report synthetically derived, structurally more complex vinblastines inaccessible from the natural product itself that are a stunning 100-fold more active (IC50 values, 50-75 pM vs. 7 nM; HCT116), and that are now accessible because of advances in the total synthesis of the natural product. The newly discovered ultrapotent vinblastines, which may look highly unusual upon first inspection, bind tubulin with much higher affinity and likely further disrupt the tubulin head-to-tail ?/? dimer-dimer interaction by virtue of the strategic placement of an added conformationally well-defined, rigid, and extended C20' urea along the adjacent continuing protein-protein interface. In this case, the added molecular complexity was used to markedly enhance target binding and functional biological activity (100-fold), and likely represents a general approach to improving the properties of other natural products targeting a protein-protein interaction.

SUBMITTER: Carney DW

PROVIDER: S-EPMC5024590 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Ultrapotent vinblastines in which added molecular complexity further disrupts the target tubulin dimer-dimer interface.

Carney Daniel W DW Lukesh John C JC Brody Daniel M DM Brütsch Manuela M MM Boger Dale L DL

Proceedings of the National Academy of Sciences of the United States of America 20160810 35

Approaches to improving the biological properties of natural products typically strive to modify their structures to identify the essential pharmacophore, or make functional group changes to improve biological target affinity or functional activity, change physical properties, enhance stability, or introduce conformational constraints. Aside from accessible semisynthetic modifications of existing functional groups, rarely does one consider using chemical synthesis to add molecular complexity to ...[more]

PMID: 27512044

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Project description:Microtubules are long polymers of alphabeta-tubulin heterodimers. They undergo a process known as dynamic instability, in which the ends of a microtubule switch stochastically between phases of slow growth and rapid shrinkage. The molecular mechanisms inducing the depolymerization of microtubules were attributed to the hydrolysis of the guanosine triphosphate (GTP) nucleotide bound to the beta-tubulin. The hydrolysis of GTP is thought to cause microtubule instability by promoting outward curving of the protofilaments constituting the microtubule lattice. The bending of protofilaments is associated with the structural transformation of a tubulin dimer from straight to curved conformations. However, the nature of intrinsic bending of the dimer remains elusive. This study uses molecular dynamics (MD) simulations and coarse-grained analysis to reveal the intrinsic bending, as well as the local structural rearrangements, of the unassembled tubulin dimer as the dimer relaxes from its lattice-constrained, straight conformation of a zinc-induced tubulin sheet. The effect of the nucleotide state on dimer-bending is investigated by the introduction of gamma-phosphate into the beta-tubulin to form GTP-bound tubulin. In agreement with recent experimental studies that proposed nucleotide-independent curved conformations, both guanosine diphosphate (GDP)-bound and GTP-bound tubulin dimers were found to have curved conformations, but with a tendency toward smaller bending in the GTP-tubulin than in the GDP-tubulin. The perturbation induced through the introduction of gamma-phosphate is posited to play a role in straightening the intradimer bending. The local structural rearrangements of GDP-tubulin because of the bending mode of motion of the dimer reveal that one of the three functional domains, the intermediate domain, exhibits significantly lower bending deformation compared with the others, signifying a dynamic connection to the functionally defined domains.

Dataset Information

Ultrapotent vinblastines in which added molecular complexity further disrupts the target tubulin dimer-dimer interface.

Publications

Ultrapotent vinblastines in which added molecular complexity further disrupts the target tubulin dimer-dimer interface.

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