Molecular docking and dynamics simulations on the interaction of cationic porphyrin–anthraquinone hybrids with DNA G-quadruplexes

Abstract

A series of cationic porphyrin-anthraquinone hybrids bearing either pyridine, imidazole, or pyrazole rings at the meso-positions have been investigated for their interaction with DNA G-quadruplexes by employing molecular docking and molecular dynamics simulations. Three types of DNA G-quadruplexes were utilized, which comprise parallel, antiparallel, and mixed hybrid topologies. The porphyrin hybrids have a preference to bind with parallel and mixed hybrid structures compared to the antiparallel structure. This preference arises from the end stacking of porphyrin moiety following G-stem and loop binding of anthraquinone tail, which is not found in the antiparallel due to the presence of diagonal and lateral loops that crowd the G-quartet. The binding to the antiparallel, instead, occurred with poorer affinity through both the loop and wide groove. All sites of porphyrin binding were confirmed by 6 ns molecular dynamics simulation, as well as by the negative value of the total binding free energies that were calculated using the MMPBSA method. Free energy analysis shows that the favorable contribution came from the electrostatic term, which supposedly originated from the interaction of either cationic pyridinium, pyrazole, or imidazole groups and the anionic phosphate backbone, and also from the van der Waals energy, which primarily contributed through end stacking interaction.

Identification of Phosphatidylinositol 3-kinase δ (PI3Kδ) Inhibitor: Pharmacophore-based Virtual Screening and Molecular Dynamics Simulation

“…kcal/mol). The binding energy value for a good inhibitor was considered in the range of -9 to -12 kcal/mol, however, the much lower binding energy value obtained in the present study corresponded to the excluded entropy term in the calculation [30]. Furthermore, the hit molecule Lig199/ZINC12638303 scored the second best binding free energy (ΔEPBTOT=-33.64± 3.69 kcal/mol), followed by the molecule hits Lig682/ZINC98047241 (ΔEPBTOT=-29.80±3.97 kcal/mol), Lig25/ZINC253496376 (ΔEPBTOT=-25.05±4.96 kcal/mol), and Lig449/ZINC85878 047 (ΔEPBTOT=-16.58±5.96 kcal/mol).…”

“…The binding affinity of ligands to PI3Kδ was assessed through the binding free energy calculation using the Molecular Mechanics-Poisson Boltzmann solvent accessible surface area (MM-PBSA) method [29][30] of AMBER16 [31]. Trajectories with two hundred snapshots were taken from 30-50 ns MD simulation.…”

Recent Developments and Applications of the MMPBSA Method

“…The interactions of histone-derived antimicrobial peptides buforin II and DesHDAP1 with DNA were also investigated (Sim et al, 2017 ). Basic mechanistic studies were carried out, including cationic porphyrin-anthraquinone hybrids binding to DNA duplexes (Arba and Tjahjono, 2015 ) and G-quadruplexes (Arba et al, 2016 ), as well as ligands binding to riboswitches upon mutation (Hu et al, 2017 ). The interactions of reactive metabolites of anticancer compounds with DNA were also analyzed (Tumbi et al, 2014 ).…”

Interaction of cationic porphyrin-imidazophenazine conjugates with DNA quadruplex: FID assay and quantum-chemical modeling

“…Usually molecular modeling of quadruplex nucleic acids and their complexes is carried out by molecular dynamics (MD) approaches [50,51]. For example, a series of cationic porphy-rin-anthraquinone hybrids have been investigated for their interaction with G4 DNA by employing docking and molecular dynamics methods [52]. MD simulations provide valuable information on conformation, dynamics and thermodynamic parameters of the systems studied.…”