TY - JOUR
T1 - GW-2974 and SCH-442416 modulators of tyrosine kinase and adenosine receptors can also stabilize human telomeric G-quadruplex DNA
AU - Salem, Alaa A.
AU - El Haty, Ismail A.
AU - Ghattas, Mohammad A.
N1 - Publisher Copyright:
Copyright: © 2022 Salem et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2022/12
Y1 - 2022/12
N2 - GW-2974 is a potent tyrosine kinase receptor inhibitor while SCH-442416 is a potent adenosine receptors’ antagonist with high selectivity towards human adenosine A2A receptor over other adenosine receptors. The two compounds were reported to possess anti-cancer properties. This study aimed to investigate whether stabilization of human telomeric G-quadruplex DNA by GW-2974- and SCH-442416 is a plausible fundamental mechanism underlying their anti-cancer effects. Human telomeric G-quadruplex DNA with sequence AG3(TTAGGG)3 was used. The study used ultraviolet-visible (UV-Vis), fluorescence, fluorescence quenching, circular dichroism (CD), melting temperatures (Tm) and molecular docking techniques to evaluate interactions. The results showed that GW-2974 and SCH-442416 interacted with G-quadruplex DNA through intercalation binding into two types of dependent binding sites. Binding affinities of 1.3 × 108-1.72 × 106 M−1 and 1.55 × 107-3.74 × 105 M−1 were obtained for GW-2974 and SCH-442416, respectively. An average number of binding sites between 1 and 2 was obtained. Additionally, the melting temperature curves indicated that complexation of both compounds to G-quadruplex DNA provided more stability (ΔTm = 9.9∘C and 9.6∘C, respectively) compared to non-complexed G-quadruplex DNA. Increasing the molar ratios over 1:1 (drug:G-quadruplex) showed less stabilization effect on DNA. Furthermore, GW-2974 and SCH-442516 have proven ≥ 4.0 folds better selective towards G-quadruplex over double-stranded ct-DNA. In silico molecular docking and dynamics revealed favorable exothermic binding for the two compounds into two sites of parallel and hybrid G-quadruplex DNA structures. The results supported the hypothesis that GW-2974 and SCH-442416 firmly stabilize human telomeric G-quadruplex DNA in additions to modulating tyrosine kinase and adenosine receptors. Consequently, stabilizing G-quadruplex DNA could be a mechanism underlying their anti-cancer activity.
AB - GW-2974 is a potent tyrosine kinase receptor inhibitor while SCH-442416 is a potent adenosine receptors’ antagonist with high selectivity towards human adenosine A2A receptor over other adenosine receptors. The two compounds were reported to possess anti-cancer properties. This study aimed to investigate whether stabilization of human telomeric G-quadruplex DNA by GW-2974- and SCH-442416 is a plausible fundamental mechanism underlying their anti-cancer effects. Human telomeric G-quadruplex DNA with sequence AG3(TTAGGG)3 was used. The study used ultraviolet-visible (UV-Vis), fluorescence, fluorescence quenching, circular dichroism (CD), melting temperatures (Tm) and molecular docking techniques to evaluate interactions. The results showed that GW-2974 and SCH-442416 interacted with G-quadruplex DNA through intercalation binding into two types of dependent binding sites. Binding affinities of 1.3 × 108-1.72 × 106 M−1 and 1.55 × 107-3.74 × 105 M−1 were obtained for GW-2974 and SCH-442416, respectively. An average number of binding sites between 1 and 2 was obtained. Additionally, the melting temperature curves indicated that complexation of both compounds to G-quadruplex DNA provided more stability (ΔTm = 9.9∘C and 9.6∘C, respectively) compared to non-complexed G-quadruplex DNA. Increasing the molar ratios over 1:1 (drug:G-quadruplex) showed less stabilization effect on DNA. Furthermore, GW-2974 and SCH-442516 have proven ≥ 4.0 folds better selective towards G-quadruplex over double-stranded ct-DNA. In silico molecular docking and dynamics revealed favorable exothermic binding for the two compounds into two sites of parallel and hybrid G-quadruplex DNA structures. The results supported the hypothesis that GW-2974 and SCH-442416 firmly stabilize human telomeric G-quadruplex DNA in additions to modulating tyrosine kinase and adenosine receptors. Consequently, stabilizing G-quadruplex DNA could be a mechanism underlying their anti-cancer activity.
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U2 - 10.1371/journal.pone.0277963
DO - 10.1371/journal.pone.0277963
M3 - Article
C2 - 36476719
AN - SCOPUS:85143564842
SN - 1932-6203
VL - 17
JO - PLoS ONE
JF - PLoS ONE
IS - 12 December
M1 - e0277963
ER -
