Article abstract
Nature Chemistry 1, 642 - 648 (2009)
Published online: 23 October 2009 | doi:10.1038/nchem.401
Subject Categories: Biochemistry | Physical chemistry | Theoretical chemistry
In silico design of tubulin-targeted antimitotic peptides
Stefano Pieraccini1, Giorgio Saladino1, Graziella Cappelletti2, Daniele Cartelli2, Pierangelo Francescato3, Giovanna Speranza3, Paolo Manitto3 & Maurizio Sironi1
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.
- Dipartimento di Chimica Fisica ed Elettrochimica, Università degli Studi di Milano, Via Golgi 19, Milano, Italy
- Dipartimento di Biologia, Università degli Studi di Milano, Via Celoria 26, Milano, Italy
- Dipartimento di Chimica Organica ed Industriale, Università degli Studi di Milano, Via Venezian 21, Milano, Italy
Correspondence to: Maurizio Sironi1 e-mail: maurizio.sironi@unimi.it
