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Modeling the binding of protoporphyrin IX, verteporfin, and chlorin e6 to SARS-CoV-2 proteins.

ABSTRACT: In this work, we analyze the latest data on the molecular docking of a range of SARS-CoV-2 proteins to protoporphyrin IX, verteporfin, and chlorin e6, as well as consider the prospects for using chlorins and porphyrins as agents for photoinactivation of the SARS2 virus.

SUBMITTER: Koifman OI

PROVIDER: S-EPMC8118678 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Modeling the binding of protoporphyrin IX, verteporfin, and chlorin e6 to SARS-CoV-2 proteins.

Koifman Oskar I OI Lebedeva Natalia Sh NS Gubarev Yury A YA Koifman Mikhail O MO

Chemistry of heterocyclic compounds 20210514 4

In this work, we analyze the latest data on the molecular docking of a range of SARS-CoV-2 proteins to protoporphyrin IX, verteporfin, and chlorin e6, as well as consider the prospects for using chlorins and porphyrins as agents for photoinactivation of the SARS2 virus. ...[more]

PMID: 34007082

Similar Datasets

Protoporphyrin IX and verteporfin potently inhibit SARS-CoV-2 infection <i>in vitro</i> and in a mouse model expressing human ACE2.

Project description:The SARS-CoV-2 infection is spreading rapidly worldwide. Efficacious antiviral therapeutics against SARS-CoV-2 is urgently needed. Here, we discovered that protoporphyrin IX (PpIX) and verteporfin, two Food and Drug Administration (FDA)-approved drugs, completely inhibited the cytopathic effect produced by SARS-CoV-2 infection at 1.25 μmol/L and 0.31 μmol/L, respectively, and their EC50 values of reduction of viral RNA were at nanomolar concentrations. The selectivity indices of PpIX and verteporfin were 952.74 and 368.93, respectively, suggesting a broad margin of safety. Importantly, PpIX and verteporfin prevented SARS-CoV-2 infection in mice adenovirally transduced with human angiotensin-converting enzyme 2 (ACE2). The compounds, sharing a porphyrin ring structure, were shown to bind viral receptor ACE2 and interfere with the interaction between ACE2 and the receptor-binding domain of viral S protein. Our study suggests that PpIX and verteporfin are potent antiviral agents against SARS-CoV-2 infection and sheds new light on developing novel chemoprophylaxis and chemotherapy against SARS-CoV-2.

| S-EPMC7724564 | biostudies-literature

Photoconduction and Electroluminescence of Copper (II) Protoporphyrin and Chlorin Cu-C-e6.

Project description:Cu (II) protoporphyrin Cu-PP-IX and chlorin Cu-C-e6 were found to have both thin solid film formation and charge carrier transport abilities. In the layers deposited by resistive thermal evaporation, the mobilities of holes and electrons are on the order of 10-5 cm2 V-1 s-1. Organic light-emitting diodes incorporating the dye molecules as emitting dopants demonstrate electroluminescence in the UV and near-IR ranges.

| S-EPMC9964107 | biostudies-literature

Binding of Immunoglobulin G to Protoporphyrin IX and Its Derivatives: Evidence the Fab Domain Recognizes the Protoporphyrin Ring.

Project description:Immunoglobulin G (IgG) is known to bind zinc via the Fc domain. In this study, biotinylated protoporphyrin IX (PPIX) was incubated with human IgG and then zinc-immobilized Sepharose beads (Zn-beads) were added to the mixture. After washing the beads, the binding of biotinylated PPIX with IgG trapped on Zn-beads was detected using alkaline phosphatase (ALP)-labeled avidin. Human IgG and its Fab domain coated on microtiter plate wells recognized biotin-labeled PPIX and its derivatives, Fe-PPIX and Zn-PPIX, whereas the Fc domain showed some extent of reaction only with Zn-PPIX. When rabbit anti-bovine transferrin (Tf) antibodies were incubated with biotinylated PPIX, the binding of anti-Tf antibodies with apo-Tf was indirectly detected using ALP-labeled avidin, suggesting that even if the antibody is modified with PPIX, the antibody-antigen reaction occurs. These results suggest that the IgG Fab domain recognizes PPIX and its derivatives, probably via the recognition of the PPIX ring. It is unlikely that binding between the Fab domain and PPIX affects the Fc domain-zinc interaction or antigen-antibody reaction.

| S-EPMC6640705 | biostudies-literature

Co-protoporphyrin IX and Sn-protoporphyrin IX inactivate Zika, Chikungunya and other arboviruses by targeting the viral envelope.

Project description:The global situation of diseases transmitted by arthropod-borne viruses such as Dengue (DENV), Yellow Fever (YFV), Chikungunya (CHIKV) and Zika (ZIKV) viruses is alarming and treatment of human infection by these arboviruses faces several challenges. The discovery of broad-spectrum antiviral molecules, able to inactivate different groups of viruses, is an interesting approach. The viral envelope is a common structure among arboviruses, being a potential target for antivirals. Porphyrins are amphipathic molecules able to interact with membranes and absorb light, being widely used in photodynamic therapy. Previously, we showed that heme, Co-protoporphyrin IX (CoPPIX) and Sn-protoporphyrin IX (SnPPIX) directly inactivate DENV and YFV infectious particles. Here we demonstrate that the antiviral activity of these porphyrins can be broadened to CHIKV, ZIKV, Mayaro virus, Sindbis virus and Vesicular Stomatitis virus. Porphyrin treatment causes viral envelope protein loss, affecting viral morphology, adsorption and entry into target cells. Also, light-stimulation enhanced the SnPPIX activity against all tested arboviruses. In summary, CoPPIX and SnPPIX were shown to be efficient broad-spectrum compounds to inactivate medically and veterinary important viruses.

| S-EPMC6023862 | biostudies-literature

Characteristics of the Protoporphyrin IX Binding Sites on Human Serum Albumin Using Molecular Docking.

Project description:Human serum albumin (HSA) is the main plasma protein responsible for a distribution of drugs in the human circulatory system. The binding to HSA is one of the factors that determines both the pharmacological actions and the side effects of drugs. The derivative of heme, protoporphyrin IX (PpIX), is a hydrophobic photosensitizer widely used in photodynamic diagnosis and therapy of various malignant disorders. Using absorption and fluorescence spectroscopy, it has been demonstrated that PpIX forms complexes with HSA. Its binding sites in the tertiary structure of HSA were found in the subdomains IB and IIA. PpIX binds to HSA in one class of binding sites with the association constant of 1.68 × 10⁵ M-1 and 2.30 × 10⁵ M-1 for an excitation at wavelength λex = 280 nm and 295 nm, respectively. The binding interactions between HSA and PpIX have been studied by means of molecular docking simulation using the CLC Drug Discovery Workbench (CLC DDWB) computer program. PpIX creates a strong 'sandwich-type' complex between its highly conjugated porphine system and aromatic side chains of tryptophan and tyrosine. In summary, fluorescent studies on binding interactions between HSA and PpIX have been confirmed by the results of computer simulation.

| S-EPMC6273174 | biostudies-literature

Molecular modeling and evaluation of binding mode and affinity of artemisinin-quinine hybrid and its congeners with Fe-protoporphyrin-IX as a putative receptor.

Project description:A recent rational approach to anti-malarial drug design is characterized as "covalent biotherapy" involves linking of two molecules with individual intrinsic activity into a single agent, thus packaging dual activity into a single hybrid molecule. In view of this background and reported anti malaria synergism between artemisinin and quinine; we describe the computer-assisted docking to predict molecular interaction and binding affinity of Artemisinin-Quinine hybrid and its derivatives with the intraparasitic haeme group of human haemoglobin. Starting from a crystallographic structure of Fe-protoporphyrin-IX, binding modes, orientation of peroxide bridge (Fe-O distance), docking score and interaction energy are predicted using the docking molecular mechanics based on generalized Born/surface area (MM-GBSA) solvation model. Seven new ligands were identified with a favourable glide score (XP score) and binding free energy (ΔG) with reference to the experimental structure from a data set of thirty four hybrid derivatives. The result shows the conformational property of the drug-receptor interaction and may lead to rational design and synthesis of improved potent artemisinin based hybrid antimalarial that target haemozoin formation.

| S-EPMC3346024 | biostudies-literature

Chlorin e6-Biotin Conjugates for Tumor-Targeting Photodynamic Therapy.

Project description:To improve the tumor-targeting efficacy of photodynamic therapy, biotin was conjugated with chlorin e6 to develop a new tumor-targeting photosensitizer, Ce6-biotin. The Ce6-biotin had good water solubility and low aggregation. The singlet-oxygen generation rate of Ce6-biotin was slightly increased compared to Ce6. Flow cytometry and confocal laser scanning microscopy results confirmed Ce6-biotin had higher binding affinity toward biotin-receptor-positive HeLa human cervical carcinoma cells than its precursor, Ce6. Due to the BR-targeting ability of Ce6-biotin, it exhibited stronger cytotoxicity to HeLa cells upon laser irradiation. The IC50 against HeLa cells of Ce6-biotin and Ce6 were 1.28 µM and 2.31 µM, respectively. Furthermore, both Ce6-biotin and Ce6 showed minimal dark toxicity. The selectively enhanced therapeutic efficacy and low dark toxicity suggest that Ce6-biotin is a promising PS for BR-positive-tumor-targeting photodynamic therapy.

| S-EPMC8658943 | biostudies-literature

Gelatin-chlorin e6 conjugate for in vivo photodynamic therapy.

Project description:BackgroundImproving the water solubility of hydrophobic photosensitizer and increasing its accumulation in tumor tissue are essential for in vivo photodynamic therapy (PDT). Considering commercialization or clinical application in future, it will be promising to achieve these purposes by developing new agents with simple and non-toxic structure.ResultsWe conjugated multiple chlorin e6 (Ce6) molecules to gelatin polymer, synthesizing two types of gelatin-Ce6 conjugates with different amounts of Ce6: gelatin-Ce6-2 and gelatin-Ce6-8. The resulting conjugates remained soluble in aqueous solutions for a longer time than hydrophobic Ce6. The conjugates could generate singlet oxygen and kill tumor cells upon laser irradiation. After intravenous injection into SCC-7 tumor-bearing mice, gelatin-Ce6-2 showed prolonged blood circulation and highly increased accumulation in tumor tissue as observed in real-time imaging in vivo. After laser irradiation, gelatin-Ce6-2 suppressed tumor growth completely and enabled improved PDT compared to free Ce6 and gelatin-Ce6-8.ConclusionsThis work demonstrates that a simple structure based on photosensitizer and gelatin can highly improve water solubility and stability. Superior tumor tissue accumulation and increased therapeutic efficacy of gelatin-Ce6 during in vivo PDT showed its high potential for clinical application.

| S-EPMC6449946 | biostudies-literature

Structural Insights into the Binding and Degradation Mechanisms of Protoporphyrin IX by the Translocator Protein TSPO.

Project description:The 18 kDa translocator protein (TSPO) has gained considerable attention as a clinical biomarker for neuroinflammation and a potential therapeutic target. However, the mechanisms by which TSPO associates with ligands, particularly the endogenous porphyrin ligand protoporphyrin IX (PpIX), remain poorly understood. In this study, we employed mutagenesis- and spectroscopy-based functional assays to investigate TSPO-mediated photo-oxidative degradation of PpIX and identify key residues involved in the reaction. We provide structural evidence using electron spin resonance, which sheds light on the highly conserved intracellular loop (LP1) connecting transmembrane 1 (TM1) and TM2. Our findings show that LP1 does not act as a lid to regulate ligand binding; instead, it interacts strongly with the TM3-TM4 linker (LP3) to stabilize the local structure of LP3. This LP1-LP3 interaction is crucial for maintaining the binding pocket structure, which is essential for proper ligand binding. Our results also demonstrate that PpIX accesses the pocket through the lipid bilayer without requiring conformational changes in TSPO. This study provides an improved understanding of TSPO-mediated PpIX degradation, highlighting potential therapeutic strategies to regulate the reaction.

| S-EPMC10598825 | biostudies-literature

Dissecting the Interactions between Chlorin e6 and Human Serum Albumin.

Project description:Chlorin e6 (Ce6) is among the most used sensitizers in photodynamic (PDT) and sonodynamic (SDT) therapy; its low solubility in water, however, hampers its clinical exploitation. Ce6 has a strong tendency to aggregate in physiological environments, reducing its performance as a photo/sono-sensitizer, as well as yielding poor pharmacokinetic and pharmacodynamic properties. The interaction of Ce6 with human serum albumin (HSA) (i) governs its biodistribution and (ii) can be used to improve its water solubility by encapsulation. Here, using ensemble docking and microsecond molecular dynamics simulations, we identified the two Ce6 binding pockets in HSA, i.e., the Sudlow I site and the heme binding pocket, providing an atomistic description of the binding. Comparing the photophysical and photosensitizing properties of Ce6@HSA with respect to the same properties regarding the free Ce6, it was observed that (i) a red-shift occurred in both the absorption and emission spectra, (ii) a maintaining of the fluorescence quantum yield and an increase of the excited state lifetime was detected, and (iii) a switch from the type II to the type I mechanism in a reactive oxygen species (ROS) production, upon irradiation, took place.

| S-EPMC10005744 | biostudies-literature

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