A more detailed picture of the interactions between virtual screening-derived hits and the DNA G-quadruplex: NMR, molecular modelling and ITC studies

Roberta Trotta; Stefano De Tito; Ilaria Lauri; Valeria La Pietra; Luciana Marinelli; Sandro Cosconati; Luigi Martino; Maria R. Conte; Luciano Mayol; Ettore Novellino; Antonio Randazzo

doi:10.1016/j.biochi.2011.05.021

A more detailed picture of the interactions between virtual screening-derived hits and the DNA G-quadruplex: NMR, molecular modelling and ITC studies

Roberta Trotta, Stefano De Tito, Ilaria Lauri, Valeria La Pietra, Luciana Marinelli, Sandro Cosconati, Luigi Martino, Maria R. Conte, Luciano Mayol, Ettore Novellino, Antonio Randazzo

University of Naples Federico II

Research output: Contribution to journal › Article › peer-review

24 Citations (Scopus)

Abstract

The growing amount of literature about G-quadruplex DNA clearly demonstrates that such a structure is no longer viewed as just a biophysical strangeness but it is instead being considered as an important target for the treatment of various human disorders such as cancers or venous thrombosis. In this scenario, with the aim of finding brand new molecular scaffolds able to interact with the groove of the DNA quadruplex [d(TGGGGT)](4), we recently performed a successful structure-based virtual screening (VS) campaign. As a result, six molecules were found to be somehow groove binders. Herein, we report the results of novel NMR titration experiments of these VS-derived ligands with modified quadruplexes, namely [d(TGG(Br)GGT)](4) and [d(TGGGG(Br)T)](4). The novel NMR spectroscopy experiments combined with molecular modelling studies, allow for a more detailed picture of the interaction between each binder and the quadruplex DNA. Noteworthy, isothermal titration calorimetry (ITC) measurements on the above-mentioned compounds revealed that 2, 4, and 6 besides their relatively small dimensions bind the DNA quadruplex [d(TGGGGT)](4) with higher affinity than distamycin A, to the best of our knowledge, the most potent groove binder identified thus far. (C) 2011 Elsevier Masson SAS. All rights reserved.

Original language	English
Pages (from-to)	1280 - 1287
Number of pages	8
Journal	Biochimie
Volume	93
Issue number	8
DOIs	https://doi.org/10.1016/j.biochi.2011.05.021
Publication status	Published - Aug 2011

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.biochi.2011.05.021

Cite this

Trotta, R., De Tito, S., Lauri, I., La Pietra, V., Marinelli, L., Cosconati, S., Martino, L., Conte, M. R., Mayol, L., Novellino, E., & Randazzo, A. (2011). A more detailed picture of the interactions between virtual screening-derived hits and the DNA G-quadruplex: NMR, molecular modelling and ITC studies. Biochimie, 93(8), 1280 - 1287. https://doi.org/10.1016/j.biochi.2011.05.021

@article{63fee8dcd518445a9887905f057324c0,

title = "A more detailed picture of the interactions between virtual screening-derived hits and the DNA G-quadruplex: NMR, molecular modelling and ITC studies",

abstract = "The growing amount of literature about G-quadruplex DNA clearly demonstrates that such a structure is no longer viewed as just a biophysical strangeness but it is instead being considered as an important target for the treatment of various human disorders such as cancers or venous thrombosis. In this scenario, with the aim of finding brand new molecular scaffolds able to interact with the groove of the DNA quadruplex [d(TGGGGT)](4), we recently performed a successful structure-based virtual screening (VS) campaign. As a result, six molecules were found to be somehow groove binders. Herein, we report the results of novel NMR titration experiments of these VS-derived ligands with modified quadruplexes, namely [d(TGG(Br)GGT)](4) and [d(TGGGG(Br)T)](4). The novel NMR spectroscopy experiments combined with molecular modelling studies, allow for a more detailed picture of the interaction between each binder and the quadruplex DNA. Noteworthy, isothermal titration calorimetry (ITC) measurements on the above-mentioned compounds revealed that 2, 4, and 6 besides their relatively small dimensions bind the DNA quadruplex [d(TGGGGT)](4) with higher affinity than distamycin A, to the best of our knowledge, the most potent groove binder identified thus far. (C) 2011 Elsevier Masson SAS. All rights reserved.",

author = "Roberta Trotta and {De Tito}, Stefano and Ilaria Lauri and {La Pietra}, Valeria and Luciana Marinelli and Sandro Cosconati and Luigi Martino and Conte, {Maria R.} and Luciano Mayol and Ettore Novellino and Antonio Randazzo",

year = "2011",

month = aug,

doi = "10.1016/j.biochi.2011.05.021",

language = "English",

volume = "93",

pages = "1280 -- 1287",

journal = "Biochimie",

publisher = "Elsevier",

number = "8",

}

Trotta, R, De Tito, S, Lauri, I, La Pietra, V, Marinelli, L, Cosconati, S, Martino, L , Conte, MR, Mayol, L, Novellino, E & Randazzo, A 2011, 'A more detailed picture of the interactions between virtual screening-derived hits and the DNA G-quadruplex: NMR, molecular modelling and ITC studies', Biochimie, vol. 93, no. 8, pp. 1280 - 1287. https://doi.org/10.1016/j.biochi.2011.05.021

TY - JOUR

T1 - A more detailed picture of the interactions between virtual screening-derived hits and the DNA G-quadruplex: NMR, molecular modelling and ITC studies

AU - Trotta, Roberta

AU - De Tito, Stefano

AU - Lauri, Ilaria

AU - La Pietra, Valeria

AU - Marinelli, Luciana

AU - Cosconati, Sandro

AU - Martino, Luigi

AU - Conte, Maria R.

AU - Mayol, Luciano

AU - Novellino, Ettore

AU - Randazzo, Antonio

PY - 2011/8

Y1 - 2011/8

N2 - The growing amount of literature about G-quadruplex DNA clearly demonstrates that such a structure is no longer viewed as just a biophysical strangeness but it is instead being considered as an important target for the treatment of various human disorders such as cancers or venous thrombosis. In this scenario, with the aim of finding brand new molecular scaffolds able to interact with the groove of the DNA quadruplex [d(TGGGGT)](4), we recently performed a successful structure-based virtual screening (VS) campaign. As a result, six molecules were found to be somehow groove binders. Herein, we report the results of novel NMR titration experiments of these VS-derived ligands with modified quadruplexes, namely [d(TGG(Br)GGT)](4) and [d(TGGGG(Br)T)](4). The novel NMR spectroscopy experiments combined with molecular modelling studies, allow for a more detailed picture of the interaction between each binder and the quadruplex DNA. Noteworthy, isothermal titration calorimetry (ITC) measurements on the above-mentioned compounds revealed that 2, 4, and 6 besides their relatively small dimensions bind the DNA quadruplex [d(TGGGGT)](4) with higher affinity than distamycin A, to the best of our knowledge, the most potent groove binder identified thus far. (C) 2011 Elsevier Masson SAS. All rights reserved.

AB - The growing amount of literature about G-quadruplex DNA clearly demonstrates that such a structure is no longer viewed as just a biophysical strangeness but it is instead being considered as an important target for the treatment of various human disorders such as cancers or venous thrombosis. In this scenario, with the aim of finding brand new molecular scaffolds able to interact with the groove of the DNA quadruplex [d(TGGGGT)](4), we recently performed a successful structure-based virtual screening (VS) campaign. As a result, six molecules were found to be somehow groove binders. Herein, we report the results of novel NMR titration experiments of these VS-derived ligands with modified quadruplexes, namely [d(TGG(Br)GGT)](4) and [d(TGGGG(Br)T)](4). The novel NMR spectroscopy experiments combined with molecular modelling studies, allow for a more detailed picture of the interaction between each binder and the quadruplex DNA. Noteworthy, isothermal titration calorimetry (ITC) measurements on the above-mentioned compounds revealed that 2, 4, and 6 besides their relatively small dimensions bind the DNA quadruplex [d(TGGGGT)](4) with higher affinity than distamycin A, to the best of our knowledge, the most potent groove binder identified thus far. (C) 2011 Elsevier Masson SAS. All rights reserved.

U2 - 10.1016/j.biochi.2011.05.021

DO - 10.1016/j.biochi.2011.05.021

M3 - Article

VL - 93

SP - 1280

EP - 1287

JO - Biochimie

JF - Biochimie

IS - 8

ER -

A more detailed picture of the interactions between virtual screening-derived hits and the DNA G-quadruplex: NMR, molecular modelling and ITC studies

Abstract

UN SDGs

Access to Document

Fingerprint

Cite this