Banerjee, Mithu and Poddar, Asim and Mitra, Gopa and Surolia, Avadhesha and Owa, Takashi and Bhattacharyya, Bhabatarak (2005) Sulfonamide Drugs Binding to the Colchicine Site of Tubulin: Thermodynamic Analysis of the Drug-Tubulin Interactions by Isothermal Titration Calorimetry. In: Journal Of Medicinal Chemistry, 48 (2). pp. 547-555.
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The discovery of several sulfonamide drugs paved the way toward thesynthesis of 6(N-12-[(4-hydroxyphenyl)amino]-3-pyridinyl]-4-methoxybenzenesulfonamide:E7010) and 7(N-(3fluoro-4-methoxyphenyl)pentafluorobenzenesulfonamide, T138067),both of which inhibit, tubulin polymerization and are under clinicaldevelopment. A series of diarylsulforiamides containing an indolescaffold was also found to have antimitotic properties, but, their modeof interactions with tubulin has remained unidentified so far. In thisstudy: we demonstrate that these sulfonamide drugs bind to thecolchicine site of tubulin in a reversible manner. They quenchedintrinsic tryptophan fluorescence of tubulin presumably due todrug-induced conformational changes in the protein, but were unable tomodulate GTPase activity of tubulin in contrast to colchicine thatenhances the same enzymatic activity. Further investigation usingisothermal titration calorimetry (ITC) revealed that 5(N-(5-chloro-7-indolyl)-4-methoxybenzenesulfonamide) afforded a largepositive value of heat capacity change $ (\Delta C_p) = +264, cal mol^-^1 K^-^1)$ on binding to tubulin, suggesting a substantial conformationaltransition in the protein along with partial enthalpy- entropycompensation. On the other hand. the 2-chloro regioisomer 2 gave alarge negative value of $\Delta C_p(-589 cal mol^-^1 K^-^1)$ along withcomplete enthalpyentropy compensation. This thermodynamic profile wasthought to be attributable to a prominent contribution of van der Waalsinteraction and hydrogen bonding between Specific groups in thedrug-tubulin complex. These results indicate that a mere alteration inthe position of a single substituent chlorine on the indole scaffoldhas a great influence on the drug-tublin binding thermodynamics.
|Item Type:||Journal Article|
|Additional Information:||The copyright for this article belongs to American Chemical Society.|
|Department/Centre:||Division of Biological Sciences > Molecular Biophysics Unit|
|Date Deposited:||25 Feb 2005|
|Last Modified:||20 Jan 2012 05:35|
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