CSBB-ConeExclusion, Adapting Structure Based Solution Virtual Screening to Libraries on Solid Support

Combinatorial chemical libraries produced on solid support offer
fast and cost-effective access to a large number of unique compounds.
If such libraries are screened directly on-bead, the speed at which
chemical space can be explored by chemists is much greater than that
addressable using solution based synthesis and screening methods.
Solution based screening has a large supporting body of software such
as structure-based virtual screening tools which enable the prediction
of protein–ligand complexes. Use of these techniques to predict
the protein bound complexes of compounds synthesized on solid support
neglects to take into account the conjugation site on the small molecule
ligand. This may invalidate predicted binding modes, the linker may
be clashing with protein atoms. We present CSBB-ConeExclusion, a methodology
and computer program which provides a measure of the applicability
of solution dockings to solid support. Output is given in the form
of statistics for each docking pose, a unique 2D visualization method
which can be used to determine applicability at a glance, and automatically
generated PyMol scripts allowing visualization of protein atom incursion
into a defined exclusion volume. CSBB-ConeExclusion is then exemplarically
used to determine the optimum attachment point for a purine library
targeting cyclin-dependent kinase 2 CDK2.