ABCB1 Structural Models, Molecular Docking, and Synthesis
of New Oxadiazolothiazin-3-one Inhibitors
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Abstract
Docking methods are powerful tools
for in silico screening and
drug lead generation and optimization. Here, we describe the synthesis
of new inhibitors of ABCB1 whose design was based on construction
and preliminary confirmation of a model for this membrane transporter
of the ATP-binding cassette family. We chose the strategy to build
our three-dimensional model of the ABCB1 transporter by homology.
Atomic coordinates were then assayed for their reliability using the
measured activity of some oxadiazolothiazin-3-one compounds. Once
established their performance by docking analysis, we synthesized
new compounds whose forecasted activity was tested by MTT and cytofluorimetric
assays. Our docking model of MDR1, MONBD1, seems to reliably satisfy
our need to design and forecast, on the basis of their LTCC blockers
ability, the inhibitory activity of new molecules on the ABCB1 transporter
