Computational chemistry approaches for discovering new antitubulin compounds

In the rational drug discovery programs, Computer-Aided Drug Design (CADD) has been to be increasingly applied. Indeed, the declining costs of memory and storage, increasing processing power and facile computer graphics software, allowed CADD to be extensively used by several pharmaceutical and academic groups. It is important to emphasize that there is no one best computational drug design technique. Many methods are used at various stages of the drug design project depending on the biological targets. During my Ph.D. thesis, I have been involved in several projects, using different approaches: 3D-QSAR, virtual screening, molecular docking and de novo drug design. In particular, my main target has been the discovery of new antitutulinic agents, acting on the colchi site, not structurally correlated with known drugs (e.g. colchine, podophyllotoxin, combretastatin A-4, chalcones). Tubulin is a heterodimeric protein, which can exist as α,β-dimers, giving rise to microtubules in a dynamic equilibrium. Polymerization into microtubules provides the main constituents of the mitotic spindle, which explains the crucial role of this protein in cellular division. Compounds that interfere with this equilibrium, either by stabilizing the microtubules or inhibiting their formation, are interesting as potential anticancer drugs. For this reason, tubulin is a major target in the field of anticancer agents. We have decided to perform a virtual screening approach on tubulin, using different commercial dataset containing about half million compounds. This database was filtered using our pharmacophoric model to discover new antitubulinic agents. The results obtained will be discussed. The second goal was to predict the binding orientation of several ligands against tubulin developed in my research group. This endeavor, if successful, will provide an enormous benefit to improve the binding affinity of these new class of compounds. Over the last five years, our research group replaced the olefinic double bond of combretastatin A-4 with different heterocycle rings (e.g. furazan, furan, triazole) obtaining novel potent antitubulinic agents. The analysis of the binding mode of all these class of compounds inside the colchi-site will be presented. References 1. Tron G.C., Pagliai F., Del Grosso E., Genazzani A.A., Sorba G.; Synthesis and cytotoxic evaluation of combretafurazans; J. Med. Chem., 2005, 48, 3260-3268 2. Tron G.C., Pirali T., Sorba G., Pagliai F., Busacca S., Genazzani A.A.; Medicinal chemistry of combretastatin A-4: present and future directions; J. Med. Chem., 2006, 49, 3033-3044 3. Pirali T., Busacca S., Beltrami L., Imovilli D., Pagliai F., Miglio G., Massarotti A., Verotta L., Tron G.C., Sorba G., Genazzani A.A.; Synthesis and cytotoxic evaluation of combretafurans, potential scaffolds for dual-action antitumoral agents; J. Med. Chem., 2006, 49, 5372-5376 4. Cafici L., Pirali T., Condorelli F., Del Grosso E., Massarotti A., Sorba G., Canonico P.L., Tron G.C., Genazzani A.A.; Solution-phase parallel synthesis and biological evaluation of combretatriazoles; J. Comb. Chem., 2008, 10, 732-740