Abstract
Targeting guanine (G)-rich DNA sequences, folded into non-canonical G-quadruplex (G4) structures, by small ligand molecules is a potential strategy for gene therapy of cancer disease. BRACO-19 has been recently established as a unique (thermodynamically favorable and highly selective) binder, being involved in the external stacking mode of interaction with a G4-DNA formed in the c-Myc oncogene promoter region (P. M. Mitrasinovic, Croat. Chem. Acta 2019, 92, 43-57). Herein, hit-to-lead ligands are identified using high-throughput virtual screening (HTVS). Search of the Kyoto Encyclopedia of Genes and Genomes (KEGG) databases is performed using the key pharmacophore features of BRACO-19. At the very outset, out of a total of 29,009 entries, 95 hits are extracted and evaluated by docking them in the binding sites of G4. Then, 22 hits are chosen by observing the binding free energies. Consequently, 3 hit-to-lead candidates are selected on the basis of structural criteria. Finally, a lead candidate structure is proposed using analog design and considering both the physicochemical requirements for optimal biological activity and a variety of pharmacological standpoints. Implications of the present study for experimental research are discussed.
Highlights
In addition to forming various canonical duplex structures, highly dynamical DNA macromolecules are able to fold into non-canonical structures, including hairpin, triplex, G-quadruplex, and i-motif
Even though G4s associate with various conformations and folding energies, and their thermodynamic stabilities are comparable to those of duplex structures, the function of G4s in vivo is not fully understood
An increasing number of identified G4-binding proteins means that protein/G4 interactions are associated with important cellular events
Summary
In addition to forming various canonical duplex structures, highly dynamical DNA macromolecules are able to fold into non-canonical structures, including hairpin, triplex, G-quadruplex, and i-motif. Even though G4s associate with various conformations and folding energies, and their thermodynamic stabilities are comparable to those of duplex structures, the function of G4s in vivo is not fully understood. G4s are hypothesized to participate in important biological phenomena, including telomere maintenance, end-capping and protection, chromosome stability, gene expression, viral integration, and recombination.[1,2] A relevant consequence of G-quadruplex formation in telomeric DNA is the inhibition of telomere elongation by telomerase in cancer cells.[3,4] An increasing number of identified G4-binding proteins means that protein/G4 interactions are associated with important cellular events. Use of small molecules for targeting G4 in order to disrupt protein/G4 recognition emerges as a potential strategy for directing anti-cancer therapy.[5]
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