title: Assignment of UV-vis spectrum of (3,3')-diindolylmethane, a Leishmania donovani topoisomerase IB inhibitor and a candidate DNA minor groove binder.
abstract: The geometrical optimization of (3,3')-diindolylmethane (DIM), an inhibitor of the bisubunit enzyme topoisomerase I from Leishmania donovani, a pathogenic protozoan parasite, mostly diffused in developing countries, has been carried out through quantum mechanical calculation. Using first-principle DFT restrained geometrical optimization, a potential energy surface has been constructed to identify a set of local minimum energy conformations of DIM. Starting from these conformations, the experimental UV-vis absorption spectrum in aqueous solution has been reproduced through TD-DFT calculations. A molecular mechanics classical force-field has been also parametrized and tested, verifying the correct coherence between the canonical ensemble obtained from molecular dynamics simulation and the potential energy surface calculation. The force field has been used to elucidate the interaction of DIM with a 22 bp DNA double strand. The best docked DIM-DNA complexes display a binding energy pretty similar to the experimental energy and are all located in the DNA minor groove, strongly suggesting that DIM is a minor groove binder.
authors.affiliation: Dipartimento di Biologia, Università degli Studi di Roma Tor Vergata, Via della Ricerca Scientifica, 00133 Roma, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Coletta
authors.forename: Blasco
authors.initials: B
authors.lastname: Morozzo della Rocca
authors.forename: Parasuraman
authors.initials: P
authors.lastname: Jaisankar
authors.forename: Hemanta K
authors.initials: HK
authors.lastname: Majumder
authors.forename: Giovanni
authors.initials: G
authors.lastname: Chillemi
authors.forename: Nico
authors.initials: N
authors.lastname: Sanna
authors.forename: Alessandro
authors.initials: A
authors.lastname: Desideri
mesh_terms: D004247:DNA / Q000737:chemistry* / Q000378:metabolism*; D004583:Electrons; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D007211:Indoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D007893:Leishmania donovani / Q000201:enzymology*; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D011789:Quantum Theory; D012996:Solutions; D013056:Spectrophotometry, Ultraviolet; D013997:Time Factors; D059004:Topoisomerase I Inhibitors
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D012996:Solutions; D059004:Topoisomerase I Inhibitors; D004247:DNA; C016392:3,3'-diindolylmethane