Interaction of cobalt(II) and copper(II) hydroxamates with polyriboadenylic acid: An insight into RNA based drug designing

Abstract

The polyadenylic acid [poly(A)] tail of mRNA plays a noteworthy role in the initiation of the translation, maturation, and stability of mRNA. It also significantly contributes to the production of alternate proteins in eukaryotic cells. Hence, it has recently been recognized as a prospective drug target. Binding affinity of bis(N-p-tolylbenzohydroxamato)Cobalt(II), [N-p-TBHA-Co(II)] (1) and bis(N-p-naphthylbenzohydroxamato)Copper(II), [N-p-NBHA-Cu(II)] (2) complexes with poly(A) have been investigated by biophysical techniques namely, absorption spectroscopy, fluorescence spectroscopy, diffuse reflectance infrared Fourier transform spectroscopy, circular dichroism spectroscopy, viscometric measurements and through molecular docking studies. The intrinsic binding constants (K_b) of complexes were determined following the order of N-p-TBHA-Co(II)] > N-p-NBHA-Cu(II), along with hyperchromism and a bathochromic shift for both complexes. The fluorescence quenching method revealed an interaction between poly(A)-N-p-TBHA-Co(II)/poly(A)-N-p-NBHA-Cu(II). The mode of binding was also determined via the fluorescence ferrocyanide quenching method. The increase in the viscosity of poly(A) that occurred from increasing the concentration of the N-p-TBHA-Co(II)/N-p-NBHA-Cu(II) complex was scrutinized. The characteristics of the interaction site of poly(A) with N-p-TBHA-Co(II)/N-p-NBHA-Cu(II) were adenine and phosphate groups, as revealed by DRS-FTIR spectroscopy. Based on these observations, a partial intercalative mode of the binding of poly(A) has been proposed for both complexes. Circular dichroism confirmed the interaction of both the complexes with poly(A). The molecular docking results illustrated that complexes strongly interact with poly(A) via the relative binding energies of the docked structure as −259.39eV and −226.30eV for N-p-TBHA-Co(II) and N-p-NBHA-Cu(II) respectively. Moreover, the binding affinity of N-p-TBHA-Co(II) is higher in all aspects than N-p-NBHA-Cu(II) for poly(A).

Graphical Abstract

KEYWORD:

• Cobalt
• Copper
• Hydroxamic acids
• Metal complexes
• Poly(A)
• Interaction
• Quenching

Acknowledgement

One of the authors, R.P. is indebted to UGC for providing BSR Faculty Fellowship Grant No. F. No. 18-1/2011(BSR). Y.T. is grateful to UGC for providing RGNF-SRF: F117.1/2014-15/RGNF-2014-15-ST-CHH-57303/(SAIII/Website) and M.T. is equally grateful to DST for providing financial assistance under scheme Inspire Fellowship (DST/INSPIRE Fellowship/2013/635). We are also thankful to UGC SAP DRS II, No.F.540/7/DRS-II/2016(SAP-1), February 2016 for providing financial assistance. M.K. Siddiqi is highly thankful to the Department of Biotechnology, India, for providing financial assistance in the form Senior Research Fellowship.