Structure-Based Virtual Screening of Novel Natural Alkaloid Derivatives as Potential Binders of h-telo and c-myc DNA G-Quadruplex Conformations

Abstract

Several ligands can bind to the non-canonical G-quadruplex DNA structures thereby stabilizing them. These molecules can act as effective anticancer agents by stabilizing the telomeric regions of DNA or by regulating oncogene expression. In order to better interact with the quartets of G-quadruplex structures, G-binders are generally characterized by a large aromatic core involved in π-π stacking. Some natural flexible cyclic molecules from Traditional Chinese Medicine have shown high binding affinity with G-quadruplex, such as berbamine and many other alkaloids. Using the structural information available on G-quadruplex structures, we performed a high throughput in silico screening of commercially available alkaloid derivative databases by means of a structure-based approach based on docking and molecular dynamics simulations against the human telomeric sequence d[AG3(T2AG3)3] and the c-myc promoter structure. We identified 69 best hits reporting an improved theoretical binding affinity with respect to the active set. Among them, OPEN ACCESSMolecules 2015, 20 207 a berberine derivative, already known to remarkably inhibit telomerase activity, was related to a better theoretical affinity versus c-myc.

G-quadruplex virtual drug screening: A review

“…When docking any library, no matter the size, there will always be “top scoring” compounds. Thus, many campaigns often use theoretical validation, such as re-docking, complimentary screening, or receiver operating characteristic [117] analyses for assessing the ability of their screen to detect real hits [48, 59, 61, 85, 118]. This is particularly important when working with small databases and can help to minimize false-positives.…”

Ligand binding to telomeric G-quadruplex DNA investigated by funnel-metadynamics simulations

“…In addition to synthetic compounds, even natural products have emerged in the last years as an invaluable source of drug candidates with over 100 natural compounds in clinical trials ( 16 ). As a result of millions of years of evolution and selection, “nature” represents an immeasurable source of chemical entities with extraordinary chemodiversity investigated by an ever-growing number of theoretical and experimental studies ( 17 – 21 ). In drug discovery, they are typically used as lead compounds to achieve more potent derivatives through structural optimization ( 22 , 23 ).…”

In Silico Screening and Binding Characterization of Small Molecules toward a G-Quadruplex Structure Formed in the Promoter Region of c-MYC Oncogene

“… 43 It was built over the template of the NMR solution structure (PDB-ID 2A5P) 25 using Maestro 45 and further details are as documented previously. 43 On the basis of the information provided in the literature, 23 , 25 , 28 , 43 the 5′ end of Pu27 was taken as the ligand binding site. A grid with an inner box (10 Å) and an outer box (30 Å) was built at the 5′ end of the quadruplex structure.…”