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

Subject Areas : Journal of Physical & Theoretical Chemistry

Z. Varmaghani ¹ , F. Mollaamin ² , L. Pishkar ³ , B. Khalili Hadda ⁴

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Received: 2015-05-09 Accepted : 2015-05-09 Published : 2008-11-01

Keywords: microtubules, Vinblastine, Monte Carlo, Molecular Dynamics, Langevin, Simulation,

Abstract :

Medicinal chemistry depends on many other disciplines ranging from organic chemistry andpharmacology to computational chemistry. Typically medicinal chemists use the moststraightforward ways to prepare compounds. The validation of any design project comes from thebiological testing.Studies of the binding site of vinblastine by a single cross—linking experiment identified it asbeing between residues 175-213 in 13—tubulin.These polypeptide residues are in the region oflateral or longitudinal contacts of protofilaments on the microtubule in the absence of a ligand. Inthe presence of vinblastine or other active vinca alkaloids a kink is formed that disturbs normalmicrotubule formation and favors depolymerization.In an effort to understand the conformational preferences that may be attributed to stereoelectroniceffects, a number of computational chemistry studies carried out. Molecular mechanics, MonteCarlo, Molecular Dynamics and Langevin calculations using the AMBER force field performedon vinblastine .These results show the minimized structure of vinblastine, calculated potentialenergy for important dihedral angles, and the effect of temperature on geometry of optimizedstructure