title: Probing the relationship between anti-Pneumocystis carinii activity and DNA binding of bisamidines by molecular dynamics simulations.
abstract: The anti-Pneumocystis carinii activity of 13 synthetic pentamidine analogs was analyzed. The experimental differences in melting points of DNA dodecamer 5'-(CGCGAATTCGCG)2-3' complexes (ΔTm), and in the biological activity measured using ATP bioluminescence assay (IC50) together with the theoretical free energy of DNA-ligand binding estimated by the proposed computational protocol, showed that the experimental activity of the tested pentamidines appeared to be due to the binding to the DNA minor groove with extended AT sequences. The effect of heteroatoms in the aliphatic linker, and the sulfonamide or methoxy substituents on the compound inducing changes in the interactions with the DNA minor groove was examined and was correlated with biological activity. In computational analysis, the explicit solvent approximation with the discrete water molecules was taken into account, and the role of water molecules in the DNA-ligand complexes was defined.
authors: Department of Organic Chemistry, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1, Warsaw 02 097, Poland. tzolek@wum.edu.pl.
authors: Teresa
authors: T
authors: Żołek
authors: Department of Organic Chemistry, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1, Warsaw 02 097, Poland. dmaciejewska@wum.edu.pl.
authors: Dorota
authors: D
authors: Maciejewska
authors: Department of Organic Chemistry, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1, Warsaw 02 097, Poland. jzabinski@wum.edu.pl.
authors: Jerzy
authors: J
authors: Żabiński
authors: Department of Organic Chemistry, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1, Warsaw 02 097, Poland. pawelkaz1@upcpoczta.pl.
authors: Paweł
authors: P
authors: Kaźmierczak
authors: Department of Organic Chemistry, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1, Warsaw 02 097, Poland. matr@o2.pl.
authors: Mateusz
authors: M
authors: Rezler
mesh_terms: D000935:Antifungal Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D005663:Furans / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D009690:Nucleic Acid Conformation; D045363:Pneumocystis carinii / Q000187:drug effects; D044366:Transition Temperature / Q000187:drug effects
chemical_list: D000935:Antifungal Agents; D005663:Furans; C469777:bisamidine; D004247:DNA