Computational Studies of Glycosylated Photosensitizers with Plasma Proteins

Abstract

Photodynamic therapy (PDT) is a promising treatment against cancer, it utilizes photosensitizers that when excited by light undergo photochemical reactions that can kill abnormal cancer cells. However, in order for photosensitizers to reach their target, they must effectively bind serum albumin, the most abundant plasma protein circulated in an organism’s blood stream. In our previous study, we synthesized three glycosylated photosensitizers (PGlu, CGlu and IGlu) and performed in vitro spectroscopy studies that revealed each glycosylated photosensitizer effectively binding bovine serum albumin and human serum albumin (BSA and HSA). The aim of this work was to implement an in silico approach to study how PGlu, CGlu, and IGlu are binding onto BSA and HSA. We performed molecular docking simulations to predict a favorable mode of binding between each of our glycosylated photosensitizers to BSA and HSA. Further, we performed a 5 ns molecular dynamics (MD) simulation for each of our predicted systems; consequently, we calculated the RMSD of the systems to attest for stability, performed binding free energy calculations to correlate with experimental binding constant results and analyzed residue interactions critical to each binding event. We observed PGlu, CGlu and IGlu favorably binding the hemin site located in subdomain IB of BSA, forming strong interactions with the Trp134 residue, as well as favorably binding Sudlow Site 1 located in subdomain IIA of HSA, forming strong interactions to Trp214. RMSD studies revealed the BSA‐IB and HSA‐IIA systems plateauing after a short time indicating stable binding events; in addition, a Pearson correlation coefficient of R=0.87 between the experimental binding constants and computational binding free energies showed a strong correlation between in vitro and in silico results. Overall, our computational results corroborated our experimental results, revealing that our glycosylated photosensitizers can bind serum albumin effectively through critical tryptophan residue interactions and can potentially aid in the progression of drug development for PDT.Support or Funding InformationThis research used resources of the National Energy Research Scientific Computing Center (NERSC), a U.S. Department of Energy Office of Science User Facility operated under Contract No. DE‐AC02‐05CH11231.