title: In search of patterns over physicochemical properties and pharmacological activities for a set of [MCl₂(thiosemicarbazone)] complexes (M=Pt/Pd): support for multiple mechanisms of antichagasic action excluding DNA-bonding in vivo?
abstract: In order to rationalize the available data related to the antichagasic activity of Pt/Pd complexes containing 5-nitrofurylthiosemicarbazones, in the present work we carried out a PCM/DFT comparative characterization of 16 Pt(II)/Pd(II) compounds of general formula [MCl(2)L] and the corresponding 5-nitrofurylthiosemicarbazone ligands (L) using multivariate techniques to sort and classify them and to search for patterns correlating the biological activity with calculated physicochemical descriptors. The data allow us to rationally propose that these compounds might act through dual or even multiple mechanisms of action, with preferred paths that depend on both the nature of metal and ligand. Moreover, these results suggest that the complexes in the set would not react in vivo with DNA, being biotransformed earlier, before gaining access to nuclear DNA in the cell. The binding mode and inhibitory potency of a selection of metal complexes and ligands with Trypanosoma cruzi cruzipain and trypanothione reductase enzymes is also modeled through molecular docking.
authors.affiliation: Laboratorio de Química Teórica y Computacional, Instituto de Química Biológica, Facultad de Ciencias, Universidad de la República, Iguá 4225, 11400 Montevideo, Uruguay.
authors.forename: Alicia
authors.initials: A
authors.lastname: Merlino
authors.forename: Lucia
authors.initials: L
authors.lastname: Otero
authors.forename: Dinorah
authors.initials: D
authors.lastname: Gambino
authors.forename: E
authors.initials: E
authors.lastname: Laura Coitiño
mesh_terms: D001665:Binding Sites; D056831:Coordination Complexes / Q000737:chemistry*; D003546:Cysteine Endopeptidases / Q000737:chemistry*; D016054:DNA, Protozoan / Q000737:chemistry; D008024:Ligands; D062105:Molecular Docking Simulation; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D010165:Palladium / Q000737:chemistry; D010984:Platinum / Q000737:chemistry; D025341:Principal Component Analysis; D011485:Protein Binding; D015800:Protozoan Proteins; D011789:Quantum Theory; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D013882:Thiosemicarbazones / Q000737:chemistry*; D014344:Trypanocidal Agents / Q000737:chemistry*; D014349:Trypanosoma cruzi / Q000737:chemistry* / Q000201:enzymology
chemical_list: D056831:Coordination Complexes; D016054:DNA, Protozoan; D008024:Ligands; D015800:Protozoan Proteins; D013882:Thiosemicarbazones; D014344:Trypanocidal Agents; D010984:Platinum; D010165:Palladium; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase; D003546:Cysteine Endopeptidases; C063214:cruzipain