Chemistry Reference
In-Depth Information
An increasing number of drug candidates (anticancer and antiinfective,
immunosuppresive, antiarthritis) are based on transition metal compounds.
Related drug discovery pioneering efforts were based on the cisplatin (famous
metallic drug) analogues. Althoug the cisplatin primary mechanism action is
based on DNA, it is much more complex than often described, since its molecular
recognition by regulatory proteins can involve many paths and biochemical
mediators [792].
Matrix metalloproteinase (MMPs) are a family of calcium-dependent, zinc-
containing endopeptidases which are responsible for the tissue remodeling and
degradation. of the extracellular matrix (ECM), including collagens, elastins,
gelatin, matrix glycoproteins, and proteo-glycan. MMPs play a crucial role in
invasion and metastasis, are upregulated in the majority of human cancers and are
involved in various pathological conditions [807].
Metal ions such as Na(+), Ca(2+) and Mg(2+), are present in milimolar
concentrations in the extracellular environment where they modulate binding of
ligands to plasma membrane receptors. Various types of ligands, including
peptide hormones and drugs, bind metal ions, in particular Ca(2+), in the lipid
milieu where it is proposed that the metal ion-bound forms of ligands represent
their bioactive conformations [808].
Inhibition of the metalloenzyme carbonic anhydrase (CA) indicates
pharmacologic applications such as anti-convulsant, anti-cancer, anti-glaucoma
agents as well as potential for anti-infective drugs (anti-bacterial and anti-fungal
agents). Sulphonamides and their isosteres (sulphamates/sulphamides) constitute
the main class of CA inhibitors (CAIs). From the enzyme active site they bind to
the metal dithiocarbamates (DTCs) inhibitors, with similar action mechanisms.
Because of covalency, ligand binding to metalloproteins could be different from
other proteins requiring appropriate docking protocols. When available and not
computationally prohibitive, quantum mechanics-based methods should give
adequate results. Grid-based methods, modification of flexible side chains,
covalent docking of reaction intermediates, geometry optimization of binding site
structures can also be used.
