On the Mechanism of Gold/NHC Compounds Binding to DNA G‐Quadruplexes: Combined Metadynamics and Biophysical Methods

Abstract

The binding modes and free-energy landscape of two Au /N-heterocyclic carbene complexes interacting with G-quadruplexes, namely a human telomeric (hTelo) and a promoter sequence (C-KIT1), are studied here for the first time by metadynamics. The theoretical results are validated by FRET DNA melting assays and provide an accurate estimate of the absolute gold complex/DNA binding free energy. This advanced in silico approach is valuable to achieve rational drug design of selective G4 binders.

A Multitarget Gold(I) Complex Induces Cytotoxicity Related to Aneuploidy in HCT‐116 Colorectal Carcinoma Cells

“…[2] Alkynyl ligands have emerged recently as promising components of gold-based drugs;h owever, the resulting alkynylgold(I) species have been much less frequently studied for therapeutic applications compared with other gold complexes. [3,4] Based on previous works on promising metal-based drugs with xanthine ligands, [5,6] thealkynyl group is linked to ac affeine unit in the target compounds described herein ( Figure 1). [*] Dr.J .-J.…”

Unveiling the Mechanisms of Aquaglyceroporin‐3 Water and Glycerol Permeation by Metadynamics

“…To this end, we used metadynamics to reconstruct the free energy of the process of interestf rom independent runs, each allowing form anifold glycerola nd water permeation events through the AQP3 pores. [42,43] To monitor and encourage the water/glycerolm olecules to explore the free energies involved in pore permeation, aC Vw as defined as the distance between centre-of-mass (COM) of the glycerolm olecules and the plane defined by four significant atoms inside the channels (see Supporting Information for details). Metadynamics accelerates event occurrencea long selected reactionc oordinates, so-called collective variables (CV), [41] and it has been recently successfully applied to calculate the free-energy surface (FES) for the interactions of drugs with DNA secondary structures.…”

“…Metadynamics accelerates event occurrencea long selected reactionc oordinates, so-called collective variables (CV), [41] and it has been recently successfully applied to calculate the free-energy surface (FES) for the interactions of drugs with DNA secondary structures. [42,43] To monitor and encourage the water/glycerolm olecules to explore the free energies involved in pore permeation, aC Vw as defined as the distance between centre-of-mass (COM) of the glycerolm olecules and the plane defined by four significant atoms inside the channels (see Supporting Information for details). Thus, al arge variation of the CV corresponded to successfult ranslocation events, from which 2D FES could be obtained.…”

Evaluation of the antiparasitic activities of imidazol‐2‐ylidene–gold(I) complexes

“…[ 7 ] Mechanistically, gold–carbene complexes can inhibit thioredoxin reductase or interact with DNA (e.g., with DNA G quadruplexes). [ 8–11 ] The high antitrypanosomal and parasite cytoskeleton‐damaging activities of cationic gold(I)–NHC complexes, such as 1a , were reported previously. [ 12 ] Complex 1a was found to be distinctly more active against Trypanosoma brucei cells than against human cells, including cancer cells.…”