Deciphering binding affinity, energetics, and base specificity of plant alkaloid Harmane with AT and GC hairpin duplex DNA

Abstract

Insights into binding efficacy and thermodynamic aspects of small molecules are important for rational drug designing and development. Here, the interaction of Harmane (Har), a very important bioactive indole alkaloid, with AT and GC hairpin duplexÀDNAs has been reported using various biophysical tools. Detailed molecular mechanism with special emphasis on binding nature, base specificity, and thermodynamics have been elucidated via probing nucleic acids with varying base compositions. Har bound to both the DNA strands exhibited hypochromic effect in absorbance whereas bathochromic and hypochromic effects in fluorescence spectra.The binding constants estimated were in the order of 10 5 M À1 (higher for GC sequence compared with AT) with 1:1 stoichiometry. Noncooperative binding mode has been observed via intercalation in both the cases. The thermodynamic profile was obtained from temperature-dependent fluorescence experiments. Both Har-AT and Har-GC complexations were exothermic in nature associated with positive entropy and negative enthalpy changes. Salt-dependent studies revealed that the binding interaction was governed by nonpolyelectrolytic and hydrophobic interaction forces. The ligand-induced structural perturbation of the DNA structures was evident from the circular dichroism data. Molecular modelling data indicated towards the involvement of hydrophobic forces and hydrogen bonding.

6‐Aryl‐Substituted Harmanium Derivatives as Light‐Up Probes for Fluorimetric DNA Detection and Staining of Eukaryotic Cells

“…This rather unusual lack of an ICD band may be explained by an accommodation of the ligand in the binding site that results only in a very weak non‐degenerative coupling of the transition dipole moments of the ligand and the base pairs [26] . Overall, these results are consistent with the DNA‐binding properties reported for harmane derivatives, which have been shown to intercalate into duplex DNA with the indole unit, while the pyrido moiety is pointing outside into the surrounding aqueous environment [5a,6b,27] …”

“…The fluorimetric DNA titrations of compounds 4 c , d revealed a significant increase of the emission intensity upon addition of ct DNA with an emission maximum at 490 nm for 4 c and 528 nm for 4 d , respectively (Figure 3B and 3 C). However, an initial slight decrease of the fluorescence intensity of derivative 4 c was observed at the beginning of the titration (Figure 3B), presumably caused by aggregation of the ligand at the DNA backbone at this very high ligand‐DNA ratio (LDR) [5a,6b] . The fluorescence quantum yields of derivative 4 c were exemplarily determined in BPE buffer ( Φ fl =0.28) and upon addition of ct DNA ( Φ fl =0.48, LDR of 3.0).…”

Structural Insight into Groove Binding of Yohimbine with Calf Thymus DNA: A Spectroscopic, Calorimetric, and Computational Approach

“…Information regarding the drug′s interaction with DNA upon binding is revealed through molecular modeling study . To understand the binding interactions, docking of the lowest-energy conformer of YH was performed with CT-DNA (PDB-ID: 1BNA) using the AutoDock 1.5.6 program. , …”

“…69 To understand the binding interactions, docking of the lowest-energy conformer of YH was performed with CT-DNA (PDB-ID: 1BNA) 88 using the AutoDock 1.5.6 program. 80,89 In each instance, docking was employed to highlight the YH binding interaction with the CT-DNA and to comprehend the underlying forces that are involved. YH compound was confirmed to exhibit a clear interaction with the naturally occurring polymeric CT-DNA, as shown in Figure 15.…”

Mechanistic investigation into the binding property of Yohimbe towards natural polymeric DNAs

“…Information regarding the drug's interaction with DNA upon binding is revealed through molecular modelling study. To understand the binding interactions, docking of the lowest energy conformer of Yh was performed with HT DNA (PDB-ID; 423D) using the AutoDock 1.5.6 program 45 , 66 . In each instance, docking was employed to highlight the Yh binding interaction with the HT DNA and to comprehend the underlying forces that are involved.…”