In silico design of tubulin-targeted antimitotic peptides

TLDR: It is shown that the application of molecular modelling techniques leads to the identification of peptides that exhibit antitubulin activity both in vitro and in cultured cells.

Abstract: Microtubules are polymeric structures formed by the self-assembly of tubulin dimers. The growth and shrinkage of these dynamic arrays have a key role during the cell-proliferation process. This makes tubulin the molecular target of many anticancer drugs currently in use or under clinical trial. Their impressive success is limited by the onset of resistant tumour cells during the treatment, so new resistance-proof molecules need to be developed. Here we use molecular dynamics and free-energy calculations to study the network of interactions that allow microtubule formation. Modelling the protein–protein interface allows us to identify the amino acids responsible for tubulin–tubulin binding and thus to design peptides, which correspond to tubulin subsequences, that interfere with microtubule formation. We show that the application of molecular modelling techniques leads to the identification of peptides that exhibit antitubulin activity both in vitro and in cultured cells. The development of molecules that target protein–protein interactions is one of the main goals of contemporary medicinal chemistry. Computational alanine scanning and molecular dynamics now leads to the identification of two peptide sequences that are important in microtubule assembly, and shows that the in silico activity can be translated into in vitro activity.