Intercalation of anticancer drug Palbociclib with calf-thymus DNA: new insights from molecular spectroscopic, molecular dynamic simulations and cleavage studies.

The interaction between the anti-cancer drug Palbociclib (PAL) and calf-thymus DNA (CT-DNA) was investigated using various biophysical techniques in a physiological buffer (pH 7.4). It was found that PAL intercalated into the base pairs of CT-DNA as evidenced from the results of UV-Vis, fluorescence, circular dichroism (CD), competitive binding assay with ethidium bromide (EB) and Hoechst 33258, KI quenching study, the effect of denaturing agent and viscosity measurements. The magnitude of binding constants (106 M-1) at different temperatures suggested strong binding between PAL and CT-DNA during complexation. The observed ΔHo > 0 and ΔSo > 0 indicated that the binding process is primarily driven by hydrophobic interactions. Molecular docking studies indicated partial intercalation of pyridopyrimidine ring between the base pairs of DNA. Free energy surface (FES) analysis derived from metadynamics simulation studies revealed the PAL-induced cleavage of DNA, which was confirmed by gel electrophoresis experiments.Communicated by Ramaswamy H. Sarma.

Multi-spectroscopic, calorimetric and molecular dynamics evaluation on non-classical intercalation of antiviral drug Molnupiravir with DNA.

The interaction of an antiviral drug Molnupiravir (MOL) with calf thymus DNA (CT-DNA) was investigated using a series of biophysical techniques. A significant hyperchromism with a blue shift nm in the UV-Vis spectra indicated a high binding affinity of MOL for CT-DNA with binding constants in the order of 105 M-1. Competitive fluorescent dye displacement assays with ethidium bromide (EB) and Hoechst 33258 suggested an intercalative mode of binding of MOL with CT-DNA. Thermodynamic profiles determined using fluorescence titration and isothermal titration calorimetric (ITC) analysis matched well with each other. The negative free energy change revealed that the MOL/CT-DNA complexation is a spontaneous process. The negative values of enthalpy and entropy changes indicated that H-bonding and van der Walls interactions play dominant roles in stabilizing the complex. A decrease in viscosity of CT-DNA solution upon adding MOL indicated a partial intercalation mode of binding which was well supported by circular dichroism (CD) spectral and effect of KI and denaturation studies. Molecular docking and metadynamics simulation studies clearly showed the partial intercalation of the pyrimidine ring of MOL into the base pairs of DNA. Free energy surface (FES) contour indicated that the drug/DNA complex is stabilized by H-bonding and pi-pi/pi-cation interactions.Communicated by Ramaswamy H. Sarma.

Multi-spectroscopic, thermodynamic and molecular simulation studies on binding of pyrroloquinoline quinone with DNA: coexistence of intercalation and groove binding modes.

The interaction between enzyme-like pyrroloquinoline quinone (PQQ) and calf-thymus DNA (CT-DNA) has been investigated by means of multi-spectroscopic (UV-Vis, fluorescence and circular dichroism), isothermal titration calorimetric (ITC), viscometry and molecular docking and metadynamics simulation techniques. Absorption spectral data suggested the formation of a PQQ/CT-DNA complex, which quenched the fluorescence of PQQ via the dynamic quenching process. The results of CD spectral studies coupled with viscosity measurements, competitive binding assays with Hoechst 33258 and ethidium bromide (EB), KI quenching experiments, gel electrophoresis and DNA melting studies indicated groove binding mode of interaction of PQQ with CT-DNA. ITC experiment revealed that the complex formation is a spontaneous process (ΔGo < 0) with a binding constant of 1.05 × 104 M-1. The observed ΔHo < 0 and ΔSo < 0 pointed out that the complex is stabilized by van der Waals forces along with H-bonding interactions. The outcomes of molecular docking and simulation studies confirmed the binding of PQQ with DNA. The free energy surface (FES) analysis pointed out the existence of an equilibrium between partial intercalation and groove binding modes, which is in good agreement with the competitive binding assays.Communicated by Ramaswamy H. Sarma.

Spectroscopic and theoretical evidences for the surface binding of voglibose drug with DNA.

Binding of voglibose (VOG), an alpha glucosidase inhibitor, with CT-DNA has been investigated using various spectroscopic techniques including UV-Vis, fluorescence and circular dichroism (CD) coupled with relative viscosity. Isothermal titration calorimetric studies have been used to calculate the thermodynamic parameters such as ΔH (0.0188 cal/mol), ΔS (63.3 cal/mol/K) and ΔG (-18.8 kcal/mol), which reveal that the binding is a spontaneous process and hydrophobic and H-bonding interactions play major roles in the binding process. Effect of ionic strength confirms the existence of hydrophobic interaction between VOG and CT-DNA. Competitive displacement assays with ethidium bromide (EB) and Hoechst 33258 suggest that VOG possibly binds on the surface of CT-DNA. Viscosity measurements also disclose that the binding could be mainly surface binding. Corroborating the experimental observations, metadynamics molecular simulation studies confirm that VOG binding on the surface of the DNA molecule through hydrophobic interactions and direct and water molecule mediated H-bonding.