Docking Ligands into Flexible and Solvated Macromolecules.
6. Development and Application to the Docking of HDACs and other Zinc
Metalloenzymes Inhibitors
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Abstract
Metalloenzymes are ubiquitous proteins
which feature one or more
metal ions either directly involved in the enzymatic activity and/or
structural properties (i.e., zinc fingers). Several members of this
class take advantage of the Lewis acidic properties of zinc ions to
carry out their various catalytic transformations including isomerization
or amide cleavage. These enzymes have been validated as drug targets
for a number of diseases including cancer; however, despite their
pharmaceutical relevance and the availability of crystal structures,
structure-based drug design methods have been poorly and indirectly
parametrized for these classes of enzymes. More specifically, the
metal coordination component and proton transfers of the process of
drugs binding to metalloenzymes have been inadequately modeled by
current docking programs, if at all. In addition, several known issues,
such as coordination geometry, atomic charge variability, and a potential
proton transfer from small molecules to a neighboring basic residue,
have often been ignored. We report herein the development of specific
functions and parameters to account for zinc–drug coordination
focusing on the above-listed phenomena and their impact on docking
to zinc metalloenzymes. These atom-type-dependent but atomic charge-independent
functions implemented into Fitted 3.1 enable the simulation
of drug binding to metalloenzymes, considering an acid–base
reaction with a neighboring residue when necessary with good accuracy