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Molecular modeling analysis of the inhibition of mitochondrial cytochrome bc1 complex activity by tocol derivatives

Abstract:

The biological functions of vitamin E related compounds have been of interest in biomedical research for several decades. Among those compounds, α-, β-, δ-, and γ-tocopherols and their oxidation products, α-, β-, δ-, γ-tocopherylquinone and their analogs α-TQo, γ-TQo, TMC20 and TMC40 were recently shown to inhibit the mitochondrial cytochrome bc1 complex. In this investigation the effects of the structural variation on the inhibition of the mitochondrial cytochrome bc1 complex were analyzed using Comparative Molecular Field Analysis (CoMFA). CoMFA performed using steric and electrostatic molecular fields produced a very good correlation. The best CoMFA models were obtained using the manual alignment of 12 compounds with 5 components (q2=0.589, SPRESS=0.515, r 2=0.992, s=0.068 and Fvalue=156.520). The resulting contour maps produced by the best CoMFA model were helpful in identifying the structural features required for the biological activity of compounds under study. These results would be helpful for pbkp_redicting the activity of new compounds, and they could be used for guiding the design, synthesis and development of new and more effective agents. © 2011 American Institute of Physics.