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Interaction of indomethacin with calf thymus DNA: a multi-spectroscopic, thermodynamic and molecular modelling approach.

ABSTRACT: Indomethacin belongs to the acetic acid derivative class of non-steroidal anti-inflammatory drugs with diverse pharmacological and biological activities. Understanding the mechanism of interaction of drugs with possible target and off-target biomolecules can prove useful in the development of a rational drug designing system. In this paper, we have attempted to ascertain the mode of binding of indomethacin with calf thymus DNA (Ct-DNA) through various biophysical techniques and in silico molecular docking. Analysis of the UV-visible absorbance spectra and fluorescence emission profile of indomethacin upon addition of Ct-DNA indicates the formation of a drug-DNA complex. UV-visible absorbance and steady state fluorescence experiments revealed a binding constant on the order of 103 L mol-1, which is consistent with those of well-known groove binders. Competitive displacement studies with ethidium bromide, acridine orange and Hoechst 33258 further suggested that indomethacin binds to the minor groove of the Ct-DNA. The above observations were further confirmed by KI induced quenching experiments, DNA melting studies, CD spectral analysis and viscosity measurements. The thermodynamic parameters like spontaneous free energy (?G < 0) and large favourable enthalpy (?H < 0) obtained from isothermal calorimetry indicated the involvement of hydrogen bonding and van der Waals forces in the binding process. Molecular docking further corroborated the experimental results.

SUBMITTER: Husain MA

PROVIDER: S-EPMC6072532 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Interaction of indomethacin with calf thymus DNA: a multi-spectroscopic, thermodynamic and molecular modelling approach.

Husain Mohammed Amir MA Ishqi Hassan Mubarak HM Sarwar Tarique T Rehman Sayeed Ur SU Tabish Mohammad M

MedChemComm 20170427 6

Indomethacin belongs to the acetic acid derivative class of non-steroidal anti-inflammatory drugs with diverse pharmacological and biological activities. Understanding the mechanism of interaction of drugs with possible target and off-target biomolecules can prove useful in the development of a rational drug designing system. In this paper, we have attempted to ascertain the mode of binding of indomethacin with calf thymus DNA (Ct-DNA) through various biophysical techniques and <i>in silico</i> ...[more]

PMID: 30108839

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Project description:Introduction: Here, the interaction behavior between propyl acridones (PA) and calf thymus DNA (ct-DNA) has been investigated to attain the features of the binding behavior of PA with ct-DNA, which includes specific binding sites, modes, and constants. Furthermore, the effects of PA on the conformation of ct-DNA seem to be quite significant for comprehending the medicine's mechanism of action and pharmacokinetics. Methods: The project was accomplished through means of absorbance studies, fluorescence spectroscopy, circular dichroism, viscosity measurement, thermal melting, and molecular modeling techniques. Results: The intercalation of PA has been suggested by fluorescence quenching and viscosity measurements results while the thermal melting and circular dichroism studies have confirmed the thermal stabilization and conformational changes that seem to be associated with the binding. The binding constants of ct-DNA-PA complex, in the absence and presence of EMF, have been evaluated to be 6.19 × 104 M-1 and 2.95 × 104 M-1 at 298 K, respectively. In the absence of EMF, the ∆H0 and ∆S0 values that occur in the interaction process of PA with ct-DNA have been measured to be -11.81 kJ.mol-1 and 51.01 J.mol-1K-1, while in the presence of EMF they were observed to be -23.34 kJ.mol-1 and 7.49 J.mol-1K-1, respectively. These numbers indicate the involvement of multiple non-covalent interactions in the binding procedure. In a parallel study, DNA-PA interactions have been monitored by molecular dynamics simulations; their results have demonstrated DNA stability with increasing concentrations of PA, as well as calculated bindings of theoretical ΔG0. Conclusion: The complex formation between PA and ct-DNA has been investigated in the presence and absence of EMF through the multi spectroscopic techniques and MD simulation. These findings have been observed to be parallel to the results of KI and NaCl quenching studies, as well as the competitive displacement with EB and AO. According to thermodynamic parameters, electrostatic interactions stand as the main energy that binds PA to ct-DNA. Regarding the cases that involve the Tm of ct-DNA, EMF has proved to increase the stability of binding between PA and ct-DNA.

Dataset Information

Interaction of indomethacin with calf thymus DNA: a multi-spectroscopic, thermodynamic and molecular modelling approach.

Publications

Interaction of indomethacin with calf thymus DNA: a multi-spectroscopic, thermodynamic and molecular modelling approach.

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