title: QSAR studies of copper azamacrocycles and thiosemicarbazones: MM3 parameter development and prediction of biological properties.
abstract: Genetic algorithms (GA) were used to develop specific copper metal-ligand force field parameters for the MM3 force field, from a combination of crystallographic structures and ab initio calculations. These new parameters produced results in good agreement with experiment and previously reported copper metal-ligand parameters for the AMBER force field. The MM3 parameters were then used to develop several quantitative structure-activity relationship (QSAR) models. A successful QSAR for predicting the lipophilicity (log P(ow)) of several classes of Cu(II)-chelating ligands was built using a training set of 32 Cu(II) radiometal complexes and 6 simple molecular descriptors. The QSAR exhibited a correlation between the predicted and experimental log P(ow) with an r(2) = 0.95, q(2) = 0.92. When applied to an external test set of 11 Cu(II) complexes, the QSAR preformed with great accuracy; r(2) = 0.93 and a q(2) = 0.91 utilizing a leave-one-out cross-validation analysis. Additional QSAR models were developed to predict the biodistribution of a smaller set of Cu(II) bis(thiosemicarbazone) complexes.
authors.affiliation: Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Wolohan
authors.forename: Jeongsoo
authors.initials: J
authors.lastname: Yoo
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Welch
authors.forename: David E
authors.initials: DE
authors.lastname: Reichert
mesh_terms: D000818:Animals; D001372:Aza Compounds / Q000737:chemistry* / Q000493:pharmacokinetics; D002614:Chelating Agents / Q000737:chemistry* / Q000493:pharmacokinetics; D003300:Copper / Q000737:chemistry; D018360:Crystallography, X-Ray; D006801:Humans; D047028:Macrocyclic Compounds / Q000737:chemistry* / Q000493:pharmacokinetics; D008954:Models, Biological; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D013882:Thiosemicarbazones / Q000737:chemistry* / Q000493:pharmacokinetics; D014018:Tissue Distribution
chemical_list: D001372:Aza Compounds; D002614:Chelating Agents; D047028:Macrocyclic Compounds; D013882:Thiosemicarbazones; D003300:Copper