Binding and interaction of dinitroanilines with apicomplexan and kinetoplastid α-tubulin

A Mitra, D Sept - Journal of medicinal chemistry, 2006 - ACS Publications
A Mitra, D Sept
Journal of medicinal chemistry, 2006ACS Publications
Despite years of use as commercial herbicides, it is still unclear how dinitroanilines interact
with tubulin, how they cause microtubule disassembly, and why they are selectively active
against plant and protozoan tubulin. In this work, through a series of computational studies,
a common binding site of oryzalin, trifluralin, and GB-II-5 on apicomplexan and kinetoplastid
α-tubulin is proposed. Furthermore, to investigate how dinitroanilines affect tubulin
dynamics, molecular dynamics simulations of Leishmania α-tubulin with and without a …
Despite years of use as commercial herbicides, it is still unclear how dinitroanilines interact with tubulin, how they cause microtubule disassembly, and why they are selectively active against plant and protozoan tubulin. In this work, through a series of computational studies, a common binding site of oryzalin, trifluralin, and GB-II-5 on apicomplexan and kinetoplastid α-tubulin is proposed. Furthermore, to investigate how dinitroanilines affect tubulin dynamics, molecular dynamics simulations of Leishmania α-tubulin with and without a bound dinitroaniline are performed. The results obtained provide insight into the molecular mechanism by which these compounds interact with tubulin and function to prevent microtubule assembly. Finally, to aid in the design of effective parasitic microtubule inhibitors, several novel dinitroaniline analogues are evaluated. The location of the binding site and the relative binding affinities of the dinitroanilines all agree well with experimental data.
ACS Publications
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