Investigating the preferential interaction between imatinib mesylate and VEGF G-quadruplex DNA as therapeutic strategies for cancer treatment: Biophysical and molecular modelling approaches.

G-Quadruplex DNA (GQ-DNA) is one of the most important non-canonical nucleic acid structures. GQ-DNA forming sequences are present in different crucial genomic regions and are abundant in promoter regions of several oncogenes. Therefore, GQ-DNA is an important target for anticancer drugs and hence binding interactions between GQ-DNA and small molecule ligands are of great importance. Since GQ-DNA is a highly polymorphic structure, it is important to identify ligand molecules which preferentially target a particular quadruplex sequence. In this present study, we have used a FDA approved drug called imatinib mesylate (ligand) which is a selective tyrosine kinase inhibitor, successfully used for the treatment of chronic myelogenous leukaemia, gastrointestinal stromal tumours. Different spectroscopic techniques as well as molecular docking investigations and molecular simulations have been used to explore the interaction between imatinib mesylate with VEGF GQ DNA structures along with duplex DNA, C-Myc, H-Telo GQ DNA. We found that imatinib mesylate shows preferential interaction towards VEGF GQ DNA compared to C-Myc, H-Telo GQ and duplex DNA. Imatinib mesylate seems to be an efficient ligand for VEGF GQ DNA, suggesting that it might be used to regulate the expression of genes in cancerous cells.

Quercetin Exhibits Preferential Binding Interaction by Selectively Targeting HRAS1 I-Motif DNA-Forming Promoter Sequences.

I-Motif (iM) DNA structures represent among the most significant noncanonical nucleic acid configurations. iM-forming DNA sequences are found in an array of vital genomic locations and are particularly frequent in the promoter islands of various oncogenes. Thus, iM DNA is a crucial candidate for anticancer medicines; therefore, binding interactions between iM DNA and small molecular ligands, such as flavonoids, are critically important. Extensive sets of spectroscopic strategies and thermodynamic analysis were utilized in the present investigation to find out the favorable interaction of quercetin (Que), a dietary flavonoid that has various health-promoting characteristics, including anticancer properties, with noncanonical iM DNA structure. Spectroscopic studies and thermal analysis revealed that Que interacts preferentially with HRAS1 iM DNA compared with VEGF, BCL2 iM, and duplex DNA. Que, therefore, emerged as a suitable natural-product-oriented antagonist for targeting HRAS1 iM DNA. The innovative spectroscopic as well as mechanical features of Que and its specific affinity for HRAS1 iM may be useful for therapeutic applications and provide crucial insights for the design of compounds with remarkable medicinal properties.

Revealing the Improved Binding Interaction of Plant Alkaloid Harmaline with Human Hemoglobin in Molecular Crowding Condition.

Harmaline and harmine are two structurally similar ß-carboline alkaloids with several therapeutic activities, such as anti-inflammatory, antioxidant, neuroprotective, nephroprotective, antidiabetic, and antitumor activities. It has been previously reported that the interaction between harmaline and hemoglobin (Hb) is weak in buffer media compared to harmine. Crowding agents induce a molecular crowding environment in the ex vivo condition, which is almost similar to the intracellular environment. In this present study, we have investigated the nature of the interactions of harmaline and harmine with Hb by increasing the percentage of the crowding agent in buffer solution. The results of the UV-vis and fluorescence spectroscopy analysis have showed that with an increasing proportion of crowding agents, the interaction between harmaline and Hb is steadily improving in comparison to harmine. It has been found that the binding constant of Hb-harmaline reaches 6.82 × 105 M-1 in the 40% polyethylene glycol 200-mediated crowding condition, indicating high affinity compared to very low interaction in buffer media. Steady-state fluorescence anisotropy along with fluorescence lifetime measurements further revealed that the rotational movement of harmaline is maximally restricted by Hb in high crowding environments. Stoichiometry results represent that Hb and harmaline interacts in a 1:1 ratio in different percentages of the crowding agent. The circular dichroism spectroscopic results predict stronger interaction of harmaline with Hb (secondary structure alterations) in a higher crowding environment. From the melting study, it was found that the reactions between Hb and harmaline in crowding environments are endothermic (ΔH > 0) and disordering (ΔS > 0) in nature, indicating that hydrogen bonding and van der Waals interactions are the main interacting forces between Hb and harmaline. Harmaline molecules are more reactive in molecular crowding conditions than in normal buffer condition. This study represents that the interaction between harmaline and Hb is stronger compared to the structurally similar harmine in a molecular crowding environment, which may enlighten the drug discovery process in cell-mimicking conditions.