From groove binding to intercalation: unravelling the weak interactions and other factors modulating the modes of interaction between methylated phenanthroline-based drugs and duplex DNA


Several antitumor drugs base their cytotoxicity on their capacity to intercalate between base pairs of DNA. Nevertheless, it has been established that the mechanism of intercalation of drugs in DNA starts with the prior groove binding mode of interaction of the drug with DNA. Sometimes, for some kind of flat small molecules, groove binding does not produce any cytotoxic effect and the fast transition of such flat small molecules to the cytotoxic intercalation mode is desirable. This is the case of methylated phenanthroline (phen) derivatives, where, changes in the substitution in the position and number of methyl groups determine their capability as cytotoxic compounds and, therefore, it is a way for the modulation of cytotoxic effects. In this work, we studied this modulation by means of the interaction of the [Pt(en)(phen)](2+) complex and several derivatives by methylation of phen in different number and position and the d(GTCGAC)(2) DNA hexamer via groove binding using PM6-DH2 and DFT-D methods. The analysis of the geometries, electronic structure and energetics of the studied systems was compared to experimental works to gain insight into the relation structure-interaction for the studied systems with cytotoxicity. The trends are explained by means of the Non-Covalent Interaction (NCI) index, the Energy Decomposition Analysis (EDA) and solvation contributions. Our results are in agreement with the experiments, in which the methylation of position 4 of phen seems to favour the interaction via groove binding thus making the transition to the intercalation cytotoxic mode difficult. Looking at the NCI results, these interactions come not only from the CH/pi and CH/n interactions of the methyl group in position 4 but also from the ethylenediamine (en) ligand, whose orientation in the Pt complex was found in such a way that it produces a high number of weak interactions with DNA, especially with the sugar and phosphate backbone.



subject category

Chemistry, Physical; Physics, Atomic, Molecular & Chemical


Sanchez-Gonzalez, A; Castro, TG; Melle-Franco, M; Gil, A

our authors


This research was financially supported by the Diputacion Foral de Gipuzkoa through the Gipuzkoa Fellows Program to A. G. This research was also financially supported by FundacAo para a Ciencia e a Tecnologia (FCT) by means of the project PTDC/QUI-QFI/29236/2017 and by the Spanish Ministry of Economy, Industry and Competitiveness under the Maria de Maeztu Units of Excellence Programme - MDM-2016-0618. Support from the Portuguese Foundation for Science and Technology (FCT), under the projects IF/00894/2015, the project CICECO-Aveiro Institute of Materials, UIDB/50011/2020 & UIDP/50011/2020, financed by national funds through the FCT/MEC and when appropriate co-financed by FEDER under the PT2020 Partnership Agreement is also gratefully acknowledged. TG Castro acknowledges FCT for the past doctoral grant (SFRH/BD/79195/2011) and the present support under the scope of the strategic funding of UIDB/04469/2020 unit.

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