Thermodynamic and structural profiles of multi‐target binding of vinblastine in solution

Abstract

Structural information about drug‐receptor interactions is paramount in drug discovery and subsequent optimization processes. Drugs can bind to multiple potential targets as they contain common chemical entities in their structures. Understanding the details of such interactions offer possibilities for repurposing and developing potent inhibitors of disease pathways. Vinblastine (VLB) is a potent anticancer molecule showing multiple receptor interactions with different affinities and degrees of structural perturbations. We have investigated the multi‐target binding profile of VLB with DNA and human serum albumin (HSA) in a dynamic physiological environment using spectroscopic, molecular dynamics simulations, and quantum mechanical calculations to evaluate the structural features, mode, ligand and receptor flexibility, and energetics of complexation. These results confirm that VLB prefers to bind in the major groove of DNA with some inclination toward Thymidine residue and the TR‐5 binding site in HSA with its catharanthine half making important contacts with both the receptors. Spectroscopic investigation at multiple temperatures has also proved that VLB binding is entropy driven indicating the major groove and TR‐5 binding site of interaction. Finally, the overall binding is facilitated by van der Waals contacts and a few conventional H‐bonds. VLB portrays reasonable conformational diversity on binding with multiple receptors.

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

“…Another important class of substances with broad-spectrum antibacterial, antiviral, anticancer, and antiprotozoal activity is nonintercalative DNA binding ligands, which exhibit various levels of sequence selectivity for binding to the DNA minor groove region. , Netropsin, distamin A, and Hoechst 33258 are some of the widely studied minor groove binding molecules that are known to attach to minor groove regions of the DNA upon AT specificity causing the minor grooves to widen. , Indole is one of the essential components found in the structure of alkaloids and several important biological molecules, including tryptophan, tryptamine, Hoechst 33258, serotonin, and gramine. They are also present in natural bioactive compounds like harmane, harmine, vinblastine, vincristine, and others. , Numerous molecules have been extensively utilized in pharmaceutical formulation. , It becomes evident that the indole ring is important for the molecules to interact with their biological receptors. Along with the primary indole ring, drug-like systems also have long side chains in their structural composition.…”

“…They are also present in natural bioactive compounds like harmane, harmine, vinblastine, vincristine, and others. 15,16 Numerous molecules have been extensively utilized in pharmaceutical formulation. 17,18 It becomes evident that the indole ring is important for the molecules to interact with their biological receptors.…”

Biophysical and structural characterization of tetramethrin serum protein complex and its toxicological implications

“…The entire process, including solvation, equilibration, and the production run, followed a well‐established MD protocol 33,34 . These MD simulations were performed in triplicate, and the data were analyzed using VMD 1.9.3 and Biovia Discovery Studio software 21,41,42 …”

“…33,34 These MD simulations were performed in triplicate, and the data were analyzed using VMD 1.9.3 and Biovia Discovery Studio software. 21,41,42…”

Insights on the comparative affinity of ribonucleic acids with plant-based beta carboline alkaloid, harmine: Spectroscopic, calorimetric and computational evaluation

“…SHAKE algorithm was not used for the production run. Both NVT and NPT equilibrations were performed for 1ns each followed by a production run of 100ns for all complexes [ [74] , [75] , [76] , [77] ]. The simulations were performed on the set parameters of 298K temperature and 1.02 atm pressure using CHARMM36 force fields [ [78] , [79] , [80] , [81] ].…”