Altering microtubule polymerization has been known to be the mechanism of action for a number of chemotherapeutically relevant drugs including taxanes and epothilones.  Recently, high-content assay platforms aimed  to monitor tubulin polymerization status by directly measuring the acute effects of drug candidates on the cellular tubulin network were developed and shown to distinguish in a quantitative manner between compounds that act as tubulin stabilizers versus those that are tubulin destabilizers.  To take advantage of the low cost involved in the production of synthetic peptides we performed of structure-based drug design (SBDD) and discovered peptides structural mimics of taxol and epothilone.  The 1tvk-B.pdb (tubulin beta chain) was used as target in docking experiments which were performed using the software SCULPT from Accelrys (originally licensed by MDL).  We first generated a library of peptides with different sequence space (including D-isomers and un-natural amino acids) and assessed the free energy of interaction between the protein target and the ligands using the MMFF94 (force-field) built-in the software SCULPT.  Both the van der Waals and the electrostatics were used to predict the relative free energy of binding between beta tubulin and the peptides ligands during rigid docking experiments.   Peptide1:  2HN-D-Trp-L-Tyr-D-Asp-Gly-L-Ser-L-Tyr-L-Gln-L-Ser-D-Ser-CONH2 and Peptide 2: 2HN-D-Tyr- L-Tyr-D-Ser-Gly- L-Ser-L-Tyr-L-Gln-L-Ser-D-Ser-CONH2 were shown to stimulate the paclitaxel activity as a tubulin stabilizer agent, by increasing the Vmax for the growth phase during tubulin polymerization in an vitro assay.  Cyclic peptides were further design from the lead linear peptides and their preliminary SBDD is presented.

Synthetic peptides alternatives to epothilone and taxol as inhibitors of the dynamics of tubulin polymerization

248th National Meeting (2014)

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