Targeting the Major Groove of the Palindromic d(GGCGCC)₂ Sequence by Oligopeptide Derivatives of Anthraquinone Intercalators

Abstract

GC-rich sequences are recurring motifs in oncogenes and retroviruses and could be targeted by noncovalent major-groove therapeutic ligands. We considered the palindromic sequence d(G 1 G 2 C 3 G 4 C 5 C 6 ) 2 , and designed several oligopeptide derivatives of the anticancer intercalator mitoxantrone. The stability of their complexes with an 18-mer oligonucleotide encompassing this sequence in its center was validated using polarizable molecular dynamics. We report the most salient structural features of two novel compounds, having a dialkylammonium group as a side chain on both arms. The anthraquinone ring is intercalated in the central d(CpG) 2 sequence with its long axis perpendicular to that of the two base pairs. On each strand, this enables each ammonium group to bind in-register to O 6 /N 7 of the two facing G bases upstream. We subsequently designed tris-intercalating derivatives, each dialkylammonium substituted with a connector to an N 9 -aminoacridine intercalator extending our target range from a six-to a ten-base-pair palindromic sequence, d(C

Enforcing Local DNA Kinks by Sequence‐Selective Trisintercalating Oligopeptides of a Tricationic Porphyrin: A Polarizable Molecular Dynamics Study**

“…We used the same procedure as described in our previous works. [14] MD simulations use the AMOEBA polarizable multipole potential [31] coded in the Tinker-HP software [12] in its recent GPU implementation. [13] We use the 2018 DNA parameters.…”

“…[37] All simulations were done on the 18-base palindromic sequence d(CGTAC GGGC GCCC GTACG) 2 , the same sequence as in the complex of a trisintercalating ligand, denoted III in our previous works. [14] Compound III is an oligopeptide derivative of an anthraquinone drug, mitoxantrone, the two arms of which were extended with an oligopeptide motif with an alkydiammonium side-chain connected by an amide-imidazole motif to an AA ring. [14] The starting trisintercalated DNA conformation was extracted from the previous MD simulation of its complex with ligand III.…”

“…[14] Compound III is an oligopeptide derivative of an anthraquinone drug, mitoxantrone, the two arms of which were extended with an oligopeptide motif with an alkydiammonium side-chain connected by an amide-imidazole motif to an AA ring. [14] The starting trisintercalated DNA conformation was extracted from the previous MD simulation of its complex with ligand III. In a first step, manual docking was performed with the help of computer graphics with the Insight II software (Accelrys Inc., San Diego).…”

“…Advances in the Tinker-HP software [12] recently operational on GPU supercomputers [13] have paved the way to long-duration MD simulations of the complexes of oligonucleotides with newlydesigned mono-and trisintercalating MTX derivatives. [14] Such simulations are now extended to bisacridinyl-bisarginyl porphyrin (BABAP) and derivatives.…”

Celebrating Diversity, Equity, Inclusion, and Respect in Computational and Theoretical Chemistry

“…A few studies in this special issue also focus on the discovery of anticancer agents. An anticancer design strategy that paves the way for designing intercalator-oligopeptide derivatives with higher selectivity is presented by El Hage and co-workers . The palindromic sequence d­(G 1 G 2 G 3 G 4 G 5 G 6 ) 2 and several oligopeptide derivatives of anticancer intercalator mitoxantrone were designed and subjected to a series of 150 ns molecular dynamics simulation using a polarizable force field.…”