Emerging protein targets for metal-based pharmaceutical agents: An update

The peculiar chemical properties of metal-based drugs impart innovative pharmacological profiles to this class of therapeutic and diagnostic agents, most likely in relation to novel molecular mechanisms still poorly understood. However, inorganic drugs have been scarcely considered for medicinal applications with respect to classical organic compounds due to the prejudice of the relevant toxic effects indicated in certain cases. Thus, the development of improved metallodrugs requires clearer understanding of their physiological processing and molecular basis of actions. Among the various issues in the area of medicinal inorganic chemistry, target elucidation and validation is essential for identifying new therapeutic and imaging applications for metal compounds, and to develop metal complexes as molecular biological tools to detect protein activities in biological systems. Recently, various proteins/enzymes were shown to be possible targets for therapeutic or diagnostic metal complexes, including metallo-enzymes and membrane water-glycerol channels (aquaporins) with essential roles in both physiological and pathophysiological states. Herein, we present an overview of the most representative studies in the field with particular focus on the emerging protein targets - namely zinc-finger proteins, aquaglyceroporins, nitric oxide synthase, thymidine kinases and carbonic anhydrases - which have been also characterized for their interactions with metal-based compounds at a molecular level via different biophysical, analytical and computational methods. A chapter is also included concerning the targeting of parasite enzymes by metal compounds for the treatment of infectious diseases.