title: A theory of mode of action of azolylalkylquinolines as DNA binding agents using automated flexible ligand docking.
abstract: Azolylalkylquinolines (AAQs) are a family of quinolines with varying degrees of cytotoxic activity (comparable or moderately superior to adriamycin in some cases) developed in the past decade in our group where their exact mode of action is still unclear. In this study the most probable DNA binding mode of AAQs was investigated employing a novel flexible ligand docking approach by using AutoDock 3.0. Forty-nine AAQs with known experimental inhibitory activity were docked onto d(CGCAAATTTGCG)(2), d(CGATCG)(2) and d(CGCG)(2) oligonucleotides retrieved from the Protein Data Bank (PDB IDs: 102D, 1D12 and 1D32, respectively) as the representatives of the three plausible models of interactions between chemotherapeutic agents and DNA (groove binding, groove binding plus intercalation and bisintercalation, respectively). Good correlation (r(2)=0.64) between calculated binding energies and experimental inhibitory activities was obtained using groove binding plus intercalation model for phenyl-azolylalkylquinoline (PAAQ) series. Our findings show that the most probable mode of action of PAAQs as DNA binding agents is via intercalation of quinolinic moiety between CG base pairs with linker chain and azole moiety binding to the minor groove.
authors.affiliation: Computational Chemistry Lab., Razi Institute for Drug Research, Iran University of Medical Sciences, Iran. armin@iums.ac.ir
authors.forename: Armin Madadkar
authors.initials: AM
authors.lastname: Sobhani
authors.forename: Sara Rasoul
authors.initials: SR
authors.lastname: Amini
authors.forename: Joel D A
authors.initials: JD
authors.lastname: Tyndall
authors.forename: Ebrahim
authors.initials: E
authors.lastname: Azizi
authors.forename: Mohsen
authors.initials: M
authors.lastname: Daneshtalab
authors.forename: Ali
authors.initials: A
authors.lastname: Khalaj
mesh_terms: D001665:Binding Sites; D003603:Cytotoxins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D004247:DNA / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D007364:Intercalating Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008024:Ligands; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D009838:Oligodeoxyribonucleotides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011804:Quinolines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D012984:Software; D013816:Thermodynamics
chemical_list: D003603:Cytotoxins; D007364:Intercalating Agents; D008024:Ligands; D009838:Oligodeoxyribonucleotides; D011804:Quinolines; D004247:DNA