Harmonization of QSAR Best Practices and Molecular Docking Provides an Efficient Virtual Screening Tool for Discovering New G-Quadruplex Ligands.
Telomeres and telomerase are key players in tumorogenesis. Among the various strategies proposed for telomerase inhibition or telomere uncapping, the stabilization of telomeric G-quadruplex (G4) structures is a very promising one. Additionally, G4 stabilizing ligands also act over tumors mediated by the alternative elongation of telomeres. Accordingly, the discovery of novel compounds able to act on telomeres and/or inhibit the telomerase enzyme by stabilizing DNA telomeric G4 structures as well as the development of approaches efficiently prioritizing such compounds constitute active areas of research in computational medicinal chemistry and anticancer drug discovery. In this direction, we applied a virtual screening strategy based on the rigorous application of QSAR best practices and its harmonized integration with structure-based methods. More than 600,000 compounds from commercial databases were screened, the first 99 compounds were prioritized, and 21 commercially available and structurally diverse candidates were purchased and submitted to experimental assays. Such strategy proved to be highly efficient in the prioritization of G4 stabilizer hits, with a hit rate of 23.5%. The best G4 stabilizer hit found exhibited a shift in melting temperature from FRET assay of +7.3 °C at 5 μM, while three other candidates also exhibited a promising stabilizing profile. The two most promising candidates also exhibited a good telomerase inhibitory ability and a mild inhibition of HeLa cells growth. None of these candidates showed antiproliferative effects in normal fibroblasts. Finally, the proposed virtual screening strategy proved to be a practical and reliable tool for the discovery of novel G4 ligands which can be used as starting points of further optimization campaigns.
ARNA Laboratory, IECB, University of Bordeaux , F-33600 Pessac, France.|ARNA Laboratory, INSERM, U869, F-33000 Bordeaux, France.
Daimel
D
Castillo-González
ARNA Laboratory, IECB, University of Bordeaux , F-33600 Pessac, France.|ARNA Laboratory, INSERM, U869, F-33000 Bordeaux, France.
Jean-Louis
JL
Mergny
ARNA Laboratory, IECB, University of Bordeaux , F-33600 Pessac, France.|ARNA Laboratory, INSERM, U869, F-33000 Bordeaux, France.
Aurore
A
De Rache
Molecular Simulation and Drug Design Group, Centro de Bioactivos Químicos (CBQ), Central University of Las Villas , Santa Clara, Villa Clara 54830, Cuba.|Department of Physiology, Faculty of Medicine, University of Valencia , Valencia 46010, Valencia, Spain.|Department of Pharmacy and Pharmaceutical Technology, University of Valencia , Burjassot 46100, Valencia, Spain.
Gisselle
G
Pérez-Machado
Molecular Simulation and Drug Design Group, Centro de Bioactivos Químicos (CBQ), Central University of Las Villas , Santa Clara, Villa Clara 54830, Cuba.|Department of Pharmacy and Pharmaceutical Technology, University of Valencia , Burjassot 46100, Valencia, Spain.|Department of Engineering, Area of Pharmacy and Pharmaceutical Technology, Miguel Hernández University , 03550 Sant Joan d'Alacant, Alicante, Alicante, Spain.
Miguel Angel
MA
Cabrera-Pérez
Dipartimento di Farmacia-Scienze, Università degli Studi di Bari "Aldo Moro″ , Via Orabona 4, 70125 Bari, Bari, Italy.
Orazio
O
Nicolotti
Dipartimento di Farmacia-Scienze, Università degli Studi di Bari "Aldo Moro″ , Via Orabona 4, 70125 Bari, Bari, Italy.
Antonellina
A
Introcaso
Dipartimento di Farmacia-Scienze, Università degli Studi di Bari "Aldo Moro″ , Via Orabona 4, 70125 Bari, Bari, Italy.
Giuseppe Felice
GF
Mangiatordi
ARNA Laboratory, IECB, University of Bordeaux , F-33600 Pessac, France.|ARNA Laboratory, INSERM, U869, F-33000 Bordeaux, France.
Aurore
A
Guédin
ARNA Laboratory, IECB, University of Bordeaux , F-33600 Pessac, France.|ARNA Laboratory, INSERM, U869, F-33000 Bordeaux, France.
Anne
A
Bourdoncle
Department of Pharmacy and Pharmaceutical Technology, University of Valencia , Burjassot 46100, Valencia, Spain.
Teresa
T
Garrigues
Department of Physiology, Faculty of Medicine, University of Valencia , Valencia 46010, Valencia, Spain.
Federico
F
Pallardó
M Natália D S
MN
Cordeiro
Instituto de Investigaciones Biomédicas (IIB), Universidad de Las Américas , 170513 Quito, Pichincha, Ecuador.
Cesar
C
Paz-Y-Miño
Instituto de Investigaciones Biomédicas (IIB), Universidad de Las Américas , 170513 Quito, Pichincha, Ecuador.
Eduardo
E
Tejera
Fernanda
F
Borges
Instituto de Investigaciones Biomédicas (IIB), Universidad de Las Américas , 170513 Quito, Pichincha, Ecuador.
Maykel
M
Cruz-Monteagudo
D000166:Acridines / Q000737:chemistry*; D049109:Cell Proliferation; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D005347:Fibroblasts / Q000737:chemistry; D054856:G-Quadruplexes; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D016615:Telomere / Q000737:chemistry
D000166:Acridines; D008024:Ligands; C454064:BRACO-19