The triazatruxene derivative azatrux binds to the parallel form of the human telomeric G-quadruplex under molecular crowding conditions: biophysical and molecular modeling studies |
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Authors: | Petraccone Luigi Fotticchia Iolanda Cummaro Annunziata Pagano Bruno Ginnari-Satriani Luca Haider Shozeb Randazzo Antonio Novellino Ettore Neidle Stephen Giancola Concetta |
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Institution: | a Dipartimento di Chimica “P. Corradini”, Università di Napoli “Federico II”, via Cintia, 4, I-80126 Napoli, Italy b Dipartimento di Scienze Farmaceutiche e Biomediche, Università di Salerno, Via Ponte Don Melillo, 84084 Fisciano (SA), Italy c Dipartimento di Chimica, Università di Roma “La Sapienza”, Piazzale A. Moro 5, 00185 Roma, Italy d Centre for Cancer Research and Cell Biology, Queen’s University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK e Dipartimento di Chimica delle Sostanze Naturali, Università di Napoli “Federico II”, Via D. Montesano 49, 80131 Napoli, Italy f Dipartimento di Chimica Farmaceutica e Tossicologica, Università di Napoli “Federico II”, Via D. Montesano 49, 80131 Napoli, Italy g Cancer Research UK Biomolecular Structure Group, The School of Pharmacy, University of London, 29-39 Brunswick Square, London WC1N 1AX, UK |
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Abstract: | The present study has employed a combination of spectroscopic, calorimetric and computational methods to explore the binding of the three side-chained triazatruxene derivative, termed azatrux, to a human telomeric G-quadruplex sequence, under conditions of molecular crowding. The binding of azatrux to the tetramolecular parallel d(TGGGGT)]4 quadruplex in the presence and absence of crowding conditions, was also characterized. The data indicate that azatrux binds in an end-stacking mode to the parallel G-quadruplex scaffold and highlights the key structural elements involved in the binding. The selectivity of azatrux for the human telomeric G-quadruplex relative to another biologically relevant G-quadruplex (c-Kit87up) and to duplex DNA was also investigated under molecular crowding conditions, showing that azatrux has good selectivity for the human telomeric G-quadruplex over the other investigated DNA structures. |
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Keywords: | G-quadruplex DNA Quadruplex-ligand interaction Molecular crowding conditions Isothermal titration calorimetry Molecular modeling Circular dichroism |
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