Computer Aided Rapid Refinement and Evaluation of Porphyrin Photosensitizers as Effective Candidates for Photodynamic Therapy

Abstract

Traditional photosensitizers (PS) in photodynamic therapy (PDT) have limited tissue penetrability of light and lacked selectivity for tumor cells, which reduces 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 medicine in PDT.

Keywords: Porphyrin-based photosensitizers, density functional theory, Molecular Docking, Photodynamic therapy, Molecular excited state