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. 2024 Sep 16;14(40):29368-29383.
doi: 10.1039/d4ra05585c. eCollection 2024 Sep 12.

Porphyrin photosensitizer molecules as effective medicine candidates for photodynamic therapy: electronic structure information aided design

Affiliations

Porphyrin photosensitizer molecules as effective medicine candidates for photodynamic therapy: electronic structure information aided design

Wei-Huang Yin et al. RSC Adv. .

Abstract

Traditional photosensitizers (PS) in photodynamic therapy (PDT) have restricted tissue penetrability of light and a lack of selectivity for tumor cells, which diminishes the efficiency of PDT. Our aim is to effectively screen porphyrin-based PS medication through computational simulations of large-scale design and screening of PDT candidates via a precise description of the state of the light-stimulated PS molecule. Perylene-diimide (PDI) shows an absorption band in the near-infrared region (NIR) and a great photostability. Meanwhile, the insertion of metal can enhance tumor targeting. Therefore, on the basis of the original porphyrin PS segments, a series of metalloporphyrin combined with PDI and additional allosteric Zn-porphyrin-PDI systems were designed and investigated. Geometrical structures, frontier molecular orbitals, ultraviolet-visible (UV-vis) absorption spectra, adiabatic electron affinities (AEA), especially the triplet excited states and spin-orbit coupling matrix elements (SOCME) of these expanded D-A porphyrin were studied in detail using the density functional theory (DFT) and time-dependent density functional theory (TDDFT) methods. PS candidates, conforming type I or II mechanism for PDT, have been researched carefully by molecular docking which targeted Factor-related apoptosis (Fas)/Fas ligand (Fasl) mediated signaling pathway. It was found that porphyrin-PDI, Fe2-porphyrin-PDI, Zn-porphyrin-PDI, Mg-porphyrin-PDI, Zn-porphyrin combined with PDI through single bond (compound 1), and two acetylenic bonds (compound 2) in this work would be proposed as potential PS candidates for PDT process. This study was expected to provide PS candidates for the development of novel medicines in PDT.

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Conflict of interest statement

There are no conflicts to declare.

Figures

Scheme 1
Scheme 1. Molecular structures of (a) M-porphyrin and (b) M-porphyrin-PDI. Fe1: singlet state; Fe2: quintet state.
Fig. 1
Fig. 1. Optimized ground-state structure of (a) M-porphyrin and (b) M-porphyrin-PDI. (c) The rotation of four benzene rings to porphyrin and the length of metal atoms to N atoms. Fe1: singlet state; Fe2: quintet state.
Fig. 2
Fig. 2. Graphical representation of the molecular orbitals of M-porphyrin and M-porphyrin-PDI.
Fig. 3
Fig. 3. Calculated frontier molecular orbital energies of ground states of (a) M-porphyrin and (b) M-porphyrin-PDI. (c) LUMO–HOMO energy gap.
Fig. 4
Fig. 4. Simulated absorption spectra of (a) M-porphyrin and (b) M-porphyrin-PDI.
Fig. 5
Fig. 5. Adiabatic electron affinities for (a) M-porphyrin and (b) M-porphyrin-PDI. The energy line of 3.73 eV for molecular oxygen was highlighted as the red dashed line.
Fig. 6
Fig. 6. Triplet excitation energies for (a) M-porphyrin and (b) M-porphyrin-PDI. The energy line of 0.98 eV, required to activate molecular oxygen, was highlighted as the black dashed line.
Fig. 7
Fig. 7. Spin–orbit coupling matrix elements between low-lying singlet and triplet excited states for (a) M-porphyrin and (b) M-porphyrin-PDI.
Scheme 2
Scheme 2. Molecular structures of compound 1–5.
Fig. 8
Fig. 8. (a) Optimized ground-state structures of compounds 1–5 and (b) illustrations of the molecular orbitals of compounds 1–5.
Fig. 9
Fig. 9. (a) Calculated absorption spectra, (b) frontier molecular orbital energies, (c) adiabatic electron affinities, (d) triplet excitation energies and (e) spin–orbit coupling matrix elements of compound 1–5.
Fig. 10
Fig. 10. Lowest energy docked positions of the PS candidates with cancer associated targeted proteins (a) Fas and (b) Fasl. The amino acid residues in the targeted proteins were shown by orange labels. Hydrogen bond interactions were represented in pink dashed lines and the corresponding hydrogen bond length values were marked.

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