Decoding the interaction of transition metal complexes with proteins is fundamental in biology, pharmacy, medicinal chemistry as well as in the design of artificial metalloenzymes. X-ray crystallography and Nuclear Magnetic Resonance (NMR) methods provide with explicit structural description of the system although their application is far from trivial. Other spectroscopic methods give insight on the protein region where the metal species is bound or on the amino acid type involved in the metal coordination. Mass spectrometry based techniques can determine the metal moieties-protein stoichiometry, and often suggest the coordinating amino acids. These instrumental techniques though are not able to provide with a complete three dimensional description of the system. _x000D_ _x000D_ This Ph.D. was aimed at expanding molecular modeling applicability to the prediction of the interaction of metallo-ligands with proteins. The thesis has been built on two major pillars. On the one hand protein-ligand docking techniques have been updated to deal with protein-metal coordination bonds formation and on the other, the resulting tools have been applied to a series of practical cases. These have been focused on the study of the interaction of vanadium based insulin-enhancing, and platinum based anti-tumor metallodrugs with their biological target, and the characterization of a copper based artificial metalloenzyme with Diels-Alderase activity. Moreover, a new integrated approach based on the combination of molecular modeling with the EPR and ESI-MS instrumental techniques, is presented. This part of the work provides with major proof-of-concept on the power of coupled experimental and theoretical approaches for the rational design of new metallodrugs as well as act as a guide in a large number of fields in bioinorganic chemistry.
Understanding the interaction of metal complexes with their biomolecular targets.
Scortino , G. (Author). 5 Dec 2019
Student thesis: Doctoral thesis
Student thesis: Doctoral thesis