Recent Insights on the Medicinal Chemistry of Metal-Based Compounds: Hints for the Successful Drug Design

M.      Z. Hernandes; F.      J.de S. Pontes; L.      C.D. Coelho; D.      R.M. Moreira; V.      R.A. Pereira; A.      C.L. Leite

Abstract

Although more complex than usually described, the anticancer action mechanism of cisplatin is based on binding to DNA. Following this line of reasoning, most the metal-based compounds discovered soon after cisplatin were designed to acting as DNA-binding agents and their pharmacological properties were thought to be correlated with this mechanism. Apart from the DNA structure, a significant number of proteins and biochemical pathways have been described as drug targets for metal-based compounds. This paper is therefore aimed at discussing the most recent findings on the medicinal chemistry of metal-based drugs. It starts illustrating the design concept behind the bioinorganic chemistry of anticancer complexes. Anticancer metallic compounds that inhibit the protein kinases are concisely discussed as a case study. The accuracy and limitations of molecular docking programs currently available to predict the binding mode of metallic complexes in molecular targets are further discussed. Finally, the advantages and disadvantages of different in vitro screenings are briefly commented.

Keywords: Metal complexes, molecular docking, organometallics, protein kinase, ruthenium, thiosemicarbazones, triapine, Metal-Based Compounds, immunosuppressive, serendipitous process, pharmacological behaviours, biochemical mediators, metal-based drugs, selenoenzyme thioredoxin reductase, anti-Malarial ferrocene, diamino-acridine, bipyridine-acridine, diamino-amidineacridine, Gold-acridine, THIOSEMICARBAZO-NES, an anticancer prototype, HAp4pT, HDpT, HAp44mT, thiosemicarbazone (centre), HApT, PROTEIN, –, META-LLIC COMPOUNDS, (source of bio-inspiration), DOCK, Multidrug resistance/resistant, PK = Protein kinases, Pgp = P-glycoprotein, RR = Ribonucleotide Reductase, SAR = Structure-activity relationships