Molecular Modeling Studies on Vinblastine Binding Site of Tubulin for Antimitotic agents

Abstract

Medicinal chemistry depends on many other disciplines ranging from organic chemistry and<br />pharmacology to computational chemistry. Typically medicinal chemists use the most<br />straightforward ways to prepare compounds. The validation of any design project comes from the<br />biological testing.<br />Studies of the binding site of vinblastine by a single cross—linking experiment identified it as<br />being between residues 175-213 in 13—tubulin.These polypeptide residues are in the region of<br />lateral or longitudinal contacts of protofilaments on the microtubule in the absence of a ligand. In<br />the presence of vinblastine or other active vinca alkaloids a kink is formed that disturbs normal<br />microtubule formation and favors depolymerization.<br />In an effort to understand the conformational preferences that may be attributed to stereoelectronic<br />effects, a number of computational chemistry studies carried out. Molecular mechanics, Monte<br />Carlo, Molecular Dynamics and Langevin calculations using the AMBER force field performed<br />on vinblastine .These results show the minimized structure of vinblastine, calculated potential<br />energy for important dihedral angles, and the effect of temperature on geometry of optimized<br />structure