DESIGN OF NOVEL TUBULIN BINDING MOLECULES AS ANTI-CANCER DRUGS AND THEIR MOLECULAR MODELING EVALUATION

Abstract

Tubulin is the target for numerous small molecule ligands which alter microtubule dynamics leading to cell cycle arrest and apoptosis. Many of these ligands are currently used clinically for the treatment of several types of cancer, and they bind to one of three distinct binding sites within β-tubulin (paclitaxel, vinca, and colchicine), all of which have been identified crystallographically. Unfortunately, serious side effects always accompany chemotherapy since these drugs bind to tubulin indiscriminately, leading to the death of both cancerous and healthy cells. However, the existence and distribution of divergent tubulin isoforms provide a platform upon which we may build novel chemotherapeutic drugs that can differentiate between different cell types and therefore reduce undesirable side effects. We report results of computational analysis that aims at predicting differences between the binding energies of a family of noscapine derivatives against 8 human α/β-tubulin isoforms. Docking and binding energy calculated using molecular mechanics generalized born surface area (MM/GB-SA) method has been used in our calculations and the results provide a proof of principle by indicating significant differences both among the derivatives and between tubulin isoforms.