Interaction of an anticancer benzopyrane derivative with DNA: Biophysical, biochemical, and molecular modeling studies

• Published in: Biochimica et biophysica acta. General subjects Vol. 1867; no. 6; p. 130347
• Main Authors: Alniss, Hasan Y., Chu, Chen, Ramadan, Wafaa S., Msallam, Yousef A., Srinivasulu, Vunnam, El-Awady, Raafat, Macgregor, Robert B., Al-Tel, Taleb H.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.06.2023
• Subjects: Benzopyrane derivatives; Calorimetry - methods; Circular dichroism (CD); DNA - chemistry; DNA Topoisomerases, Type II - metabolism; Double stranded DNA (dsDNA); Isothermal titration calorimetry (ITC); Models, Molecular; Molecular Docking Simulation; Molecular modeling; Nucleic Acid Denaturation; Salmon sperm DNA; Topoisomerases; Double stranded DNA (dsDNA); Isothermal titration calorimetry (ITC); Circular dichroism (CD); K; pDOS; PDB; sDNA; TΔS; PI3K; Rg; Molecular modeling; MD; GSHR; Salmon sperm DNA; Ras-ERK; TrxR; CD; Topoisomerases; RMSF; MGB; RMSD; AIR; Akt; Benzopyrane derivatives; ΔG; ΔH; ITC; dsDNA
• ISSN: 0304-4165; 1872-8006; 1872-8006
• DOI: 10.1016/j.bbagen.2023.130347

SIMR1281 is a potent anticancer lead candidate with multi- target activity against several proteins; however, its mechanism of action at the molecular level is not fully understood. Revealing the mechanism and the origin of multitarget activity is important for the rational identification and optimization of multitarget drugs. We have used a variety of biophysical (circular dichroism, isothermal titration calorimetry, viscosity, and UV DNA melting), biochemical (topoisomerase I & II assays) and computational (molecular docking and MD simulations) methods to study the interaction of SIMR1281 with duplex DNA structures. The biophysical results revealed that SIMR1281 binds to dsDNA via an intercalation-binding mode with an average binding constant of 3.1 × 106 M−1. This binding mode was confirmed by the topoisomerases' inhibition assays and molecular modeling simulations, which showed the intercalation of the benzopyrane moiety between DNA base pairs, while the remaining moieties (thiazole and phenyl rings) sit in the minor groove and interact with the flanking base pairs adjacent to the intercalation site. The DNA binding characteristics of SIMR1281, which can disrupt/inhibit DNA function as confirmed by the topoisomerases' inhibition assays, indicate that the observed multi-target activity might originate from ligand intervention at nucleic acids level rather than due to direct interactions with multiple biological targets at the protein level. The findings of this study could be helpful to guide future optimization of benzopyrane-based ligands for therapeutic purposes. [Display omitted] •The interaction of SIMR1281 with DNA was studied using a variety of biophysical methods.•The experimental and simulation results proved the intercalation binding mode.•The topoisomerases inhibition assays confirmed the DNA binding characteristics of SIMR1281.•The multitarget activity of SIMR1281 arises from its intervention at nucleic acids level.•A good basis to guide future optimization of benzopyrane-based ligands as therapeutic drugs.