Issue in Honor of Prof. Vincenzo Tortorella ARKIVOC 2004 (v) 263-271
Docking of indolo- and pyrrolo-pyrimidines to DNA. New DNAinteractive polycycles from amino-indoles/pyrroles and BMMA
Antonino Lauria, Patrizia Diana, Paola Barraja, Alessandra Montalbano, Gaetano Dattolo, Girolamo Cirrincione, and Anna Maria Almerico*
Dipartimento Farmacochimico, Tossicologico e Biologico Università degli Studi di Palermo, Via Archirafi 32, 90123 Palermo, Italy E-mail: almerico@unipa.it
Dedicated to Professor Vincenzo Tortorella in the occasion of his “Fuori Ruolo” status (received 05 Jan 04; accepted 29 Mar 04; published on the web 01 Apr 04)
Abstract New indolo- and pyrrolo-pyrimidines of type 1-4 were studied for their ability to form stable complexes with DNA fragments. The calculated free energies of binding were found in the range -8.39 ÷ -16.72 Kcal/mol. The docking studies revealed a common binding mode with the chromophore intercalated between GC base pairs whereas the side chain lies along the minor groove.
Keywords: Docking, DNA interaction, indolopyrimidine, pyrrolopyrimidine, aminoindoles, aminopyrroles, BMMA
Introduction
DNA represents one of the most important molecular cellular targets of several chemotherapic drugs. Molecular recognition of DNA by small molecules and proteins is a fundamental problem in drug design. Polycyclic heterocycles having a planar structure can be effective pharmacophore moieties of DNA-interactive drugs because they can insert between the stacked base paired oligonucleotides. Moreover if they bear suitable side chains further interactions of these ligands with the other important architectural feature of DNA, its minor groove, can be envisaged. Relatively little is understood at present about the mode of action at the molecular level of the majority of minor groove-interacting drugs, although there is increasing evidence that may act by directly blocking or inhibiting protein–DNA recognition.1
Among the different classes of antitumor drugs which interact with DNA the actinomycins, a family of chromopeptide antibiotics, represent a peculiar one that combines the two above mentioned features. The most representative derivative, Dactinomycin (Actinomycin D), has
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