Reactivity and Stability of Metalloporphyrin Complex Formation: DFT and Experimental Study.

The interaction of three cationic porphyrins-meso-tetrakis (N-methylpyridinium-4-yl) porphyrin (TMPyP), meso-tetrakis (1,3-dimethylimidazolium-2-yl) porphyrin (TDMImP), and meso-tetrakis (1,2-dimethylpyrazolium-4-yl) porphyrin (TDMPzP)-with five heavy metals was studied computationally, and binding constants were calculated based on data obtained by an experimental method and compared. The reactivity and stability of their complexes formed with lead, cadmium, mercury, tin, and arsenic ions were observed in DFT global chemical reactivity descriptors: the electronic chemical potential (µ), chemical hardness (η), and electrophilicity (ω). The results show that M-TDMPzP has higher chemical hardness and lower electrophilicity compared to M-TMPyP and M-TDMImP, indicating the reaction of TDMPzP with metals will form a more stable complex. Specifically, Cd-TDMPzP complexes can stabilize the system, with a lower energy and electronic chemical potential, higher chemical hardness, smaller electrophilicity, and higher binding constant value compared to Pb-TDMPzP and Hg-TDMPzP. This result suggests that the interaction of the Cd2+ ion with TDMPzP will produce a stable complex.

Pharmacophore-based virtual screening for identifying ß5 subunit inhibitor of 20S proteasome.

Proteasomal system plays an important role in maintaining cell homeostatis. Overexpression of proteasomes leads to several major diseases, such as cancer and autoimmune disorder. The ß5 subunit of proteasome is a crucial active site in proteolysis, and targeting proteasome ß5 subunit is essential for proteasome inhibition. In the present study, a pharmacophore-based virtual screening and molecular docking were employed to identify ligands as inhibitors of ß5 subunit of proteasome. The pharmacophore features were built with one hydrogen bond donor, two hydrogen bond acceptors, and one hydrophobic feature using native ligand of proteasome (HU10), which was then used to screen ZINC database using ZINCPharmer. The retrieved virtual hits were subjected to molecular docking analysis using iDock. The best six hits were subjected to molecular dynamics (MD) simulation and each complex was stable during 40 ns MD simulation as indicated by root-mean-square-deviation (RMSD) and root-mean-square-fluctuation (RMSF) values. The current study identifies 5 best hits having better binding potentials than HU10 as predicted by molecular mechanics Poisson-Boltzmann Surface Area (MM-PBSA) method, i.e. Lig1540/ZINC33356240, Lig1546/ZINC33356235, Lig1522/ZINC20854878, Lig980/ZINC12391945, and Lig1119/ZINC19865241, which can be used in the development of new proteasome inhibitors.

Computational Study of Imidazolylporphyrin Derivatives as a Radiopharmaceutical Ligand for Melanoma.

BACKGROUND: Melanoma is the most aggressive type of skin cancer. Metastatic melanoma is extremely difficult to treat with current therapy methods such as surgery. On the other hand, it is a good opportunity to develop a radiopharmaceutical using a radionuclide such as Technetium (Tc) for diagnostic and Rhenium (Re) for therapeutic purposes. T3,4BCPP has been be used as a radioimaging agent for melanoma cancers experimentally. The aim of the present research was to design new imidazolylporphyrin derivatives with better selectivity and higher affinity than those of T3,4BCPP by molecular modeling. METHODS: Eight types of Re- and Tc-labeled imidazolylporphyrins were docked to Fibroblast Growth Factor Receptor 1 (FGFR1, PDB ID: 5AM6) using AutoDock 4.2. FGFR1 was simulated by Molecular Dynamic (MD) simulation for 30 ns using NAMD 2.10 at 37 °C. The obtained conformations were then applied in a molecular docking simulation. Dovitinib (natural ligand of FGFR1), Re- and Tc-T3, 4BCPP were used as references. RESULTS: The MD simulation resulted in an RMSD of 3.8 Å. From all the studied imidazolylporphyrin derivatives, Tc-cD3, 4BCPMIP and Re-cD3, 4BCPIP had the best docking parameter. Tc-cD3, 4BCPMIP had a free binding energy of -4.06 kcal/mol, while that of Re-cD3, 4BCPIP was -4.35 kcal/mol. CONCLUSION: It is concluded that cD3,4BCPMIP and cD3,4BCPIP are two potential candidate ligands for a melanoma radiopharmaceutical kit.

Molecular modeling on porphyrin derivatives as ß5 subunit inhibitor of 20S proteasome.

The ubiquitin-proteasome system plays an important role in protein quality control. Currently, inhibition of the proteasome has been validated as a promising approach in anticancer therapy. The 20S core particle of the proteasome harbors ß5 subunit which is a crucial active site in proteolysis. Targeting proteasome ß5 subunit which is responsible for the chymotrypsin-like activity of small molecules has been regarded as an important way for achieving therapeutics target. In the present study, a series of porphyrin derivatives bearing either pyridine or pyrazole rings as meso-substituents were designed and evaluated as an inhibitor for the ß5 subunit of the proteasome by employing molecular docking and dynamics simulations. The molecular docking was performed with the help of AutoDock 4.2, while molecular dynamics simulation was done using AMBER 14. All compounds bound to the proteasome with similar binding modes, and each porphyrin-proteasome complex was stable during 30 ns MD simulation as indicated by root-mean-square-deviation (RMSD) value. An analysis on protein residue fluctuation of porphyrin binding demonstrates that in all complexes, porphyrin binding produces minor fluctuation on amino acid residues. The molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) free energy calculation shows that the binding affinities of mono-H2PyP, bis-H2PzP, and tetra-H2PyP were comparable with that of the potential inhibitor, HU10. It is noted that the electrostatic interaction increases with the number of meso-substituents, which was favourable for porphyrin binding. The present study shows that both electrostatic and van der Waals interaction are the main force which controls the interaction of porphyrin compounds with the proteasome.

Molecular modeling of cationic porphyrin-anthraquinone hybrids as DNA topoisomerase IIß inhibitors.

Human DNA Topoisomerase II has been regarded as a promising target in anticancer drug discovery. In the present study, we designed six porphyrin-anthraquinone hybrids bearing pyrazole or pyridine group as meso substituents and evaluated their potentials as DNA Topoisomerase IIß inhibitor. First, we investigated the binding orientation of porphyrin hybrids into DNA topoisomerase IIß employing AutoDock 4.2 and then performed 20-ns molecular dynamics simulations to see the dynamic stability of each porphyrin-Topo IIß complex using Amber 14. We found that the binding of porphyrin hybrids occured through intercalation and groove binding mode in addition interaction with the amino acid residues constituting the active cavity of Topo IIß. Each porphyrin-Topo IIß complex was stabilized during 20-ns dynamics simulations. The MM-PBSA free energy calculation shows that the binding affinities of porphyrin hybrids were modified with the number of meso substituent. Interestingly, the affinity of all porphyrin hybrids to Topo IIß was stronger than that of native ligand (EVP), indicating the potential of the designed porphyrin to be considered in experimental research.

A selective distance-based paper analytical device for copper(II) determination using a porphyrin derivative.

Meso-tetrakis(1,2-dimethylpyrazolium-4-yl)porphyrin sulfonate (TDMPzP), a water-soluble porphyrin derivative, was synthesized and used as a colorimetric reagent for Cu2+ detection on a microfluidic paper-based analytical device (µPAD) using distance-based quantification. TDMPzP showed a high selectivity for Cu2+ detection in aqueous solutions. When Cu2+ was added to the TDMPzP under acidic conditions, a color change from green to a pink was observed by the naked eye. Under optimized conditions, the application of this system to a distance-based µPAD exhibited good analytical response. The presence of common metal ions (Al3+, Fe3+, Mg2+, Co2+, Mn2+, Zn2+, Pb2+, Cd2+, Sn2+, and Ni2+) did not interfere with Cu2+ detection within reasonable tolerance ratios. The lowest concentration of copper that could be measured was 1mgL-1 (1ppm) which meets the requirements for drinking water contamination regulations from the US Environmental Protection Agency (EPA) and World Health Organization (WHO) guidelines for drinking water. Real drinking water samples were analyzed to confirm the practical application of this system and the results showed good agreement with ICP-MS data. This distance-based µPAD based on TDMPzP for Cu2+ detection is convenient and effective for real-time drinking water analysis.

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

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.

The binding modes of cationic porphyrin-anthraquinone hybrids to DNA duplexes: in silico study.

Cationic porphyrin-anthraquinone hybrids bearing peripheral substituents, either pyridine, imidazole, or pyrazole rings have been investigated for their binding mode to DNA duplexes. The four kinds of DNA duplexes were used, which represent intercalation and groove binding modes. AutoDock 4.2 was used to dock nine hybrid compounds to four DNA duplexes, while monitoring of conformational changes of four best hybrid-DNA complexes during 2 ns was performed by Amber9 molecular dynamics package. The binding energy calculation of best four complexes was then carried out using MMPBSA method. The hybrid compounds interacted to DNA duplexes through intercalation and groove binding modes. The minor groove binding of DNA was energetically preferred by cationic porphyrin hybrids due to favorable electrostatic and van der Waals interactions. Both electrostatic and van der Waals contributions were able to distinguish the binding mode of porphyrin hybrid to DNA duplexes.

Spectroscopic studies on the thermodynamic and thermal denaturation of the ct-DNA binding of methylene blue.

The ct-DNA binding properties of methylene blue (MB) including binding constant, thermodynamic parameter and thermal denaturation (T(m)) have been systematically studied by spectrophotometric method. The binding of MB to ct-DNA is quite strong as indicated by remarkable hypochromicity, red shift and equilibrium binding constant (K(b)). Van't Hoff plot of 1/T versus lnK(b) suggests that the MB dye binds exothermically to ct-DNA which is characterized by large negative enthalpy and entropy changes. According to polyelectrolyte theory, the charge release (Z) when ct-DNA interacts with MB is +1.09 which corresponds very well to the one positive charge carried by the MB dye. The K(b) at a low concentration of salt is dominated by electrostatic interaction (90%) while that at a high concentration of salt is mostly controlled by non-electrostatic process (85%). However, the stabilization of the DNA binding event in both cases is governed by non-electrostatic process. A moderate stabilization of double helix ct-DNA occurs when the MB dye binds to ct-DNA as indicated by the increase in T(m) of ct-DNA of about 5.5 degrees C in the presence of MB. This suggests that MB dye possibly binds to ct-DNA via electrostatic and intercalation modes.

Redox modulation of oxidative stress by Mn porphyrin-based therapeutics: the effect of charge distribution.

We evaluate herein the impact of positive charge distribution on the in vitro and in vivo properties of Mn porphyrins as redox modulators possessing the same overall 5+ charge and of minimal stericity demand: Mn(III) meso-tetrakis(trimethylanilinium-4-yl)porphyrin (MnTTriMAP(5+)), Mn(III) meso-tetrakis(N,N'-dimethylpyrazolium-4-yl)porphyrin (MnTDM-4-PzP(5+)), Mn(III) meso-tetrakis(N,N'-dimethylimidazolium-2-yl)porphyrin (MnTDM-2-ImP(5+)), and the ortho and para methylpyridinium complexes Mn(III) meso-tetrakis(N-methylpyridinium-4-yl)porphyrin (MnTM-4-PyP(5+)) and Mn(III) meso-tetrakis(N-methylpyridinium-2-yl)porphyrin (MnTM-2-PyP(5+)). Both Mn(III)/Mn(II) reduction potential and SOD activity within the series follow the order: MnTTriMAP(5+)

Binding of tetrakis(pyrazoliumyl)porphyrin and its copper(II) and zinc(II) complexes to poly(dG-dC)2 and poly(dA-dT)2.

Interactions of cationic porphyrins bearing five-membered rings at the meso position, meso-tetrakis(1,2-dimethylpyrazolium-4-yl)porphyrin (MPzP; M is H2, Cu(II) or Zn(II)), with synthetic polynucleotides poly(dG-dC)2 and poly(dA-dT)2 have been characterized by viscometric, visible absorption, circular dichroisim and magnetic circular dichroism spectroscopic and melting temperature measurements. Both H2PzP and CuPzP are intercalated into poly(dG-dC)2 and are outside-bound to the major groove of poly(dA-dT)2, while ZnPzP is outside-bound to the minor groove of poly(dA-dT)2 and surprisingly is intercalated into poly(dG-dC)2. The binding constants of the porphyrin and poly(dG-dC)2 and poly(dA-dT)2 are on the order of 10(6) M(-1) and are comparable to those of other cationic porphyrins so far reported. The process of the binding of the porphyrin to poly(dG-dC)2 and poly(dA-dT)2 is exothermic and enthalpically driven for H2PzP, whereas it is endothermic and entropically driven for CuPzP and ZnPzP. These results have revealed that the kind of the central metal ion of metalloporphyrins influences the characteristics of the binding of the porphyrins to DNA.