Molecular Docking and Molecular Dynamics Studies Reveal Secretory Proteins as Novel Targets of Temozolomide in...

Glioblastoma multiforme (GBM) is a tumor of glial origin and is the most malignant, aggressive and prevalent type, with the highest mortality rate in adult brain cancer. Surgical resection of the tumor followed by Temozolomide (TMZ) therapy is currently available, but the development of resistance to TMZ is a common limiting factor in effective treatment. The present study investigated the potential interactions of TMZ with several secretory proteins involved in various molecular and cellular processes in GBM. Automated docking studies were performed using AutoDock 4.2, which showed an encouraging binding affinity of TMZ towards all targeted proteins, with the strongest interaction and binding affinity with GDF1 and SLIT1, followed by NPTX1, CREG2 and SERPINI, among the selected proteins. Molecular dynamics (MD) simulations of protein-ligand complexes were performed via CABS-flex V2.0 and the iMOD server to evaluate the root-mean-square fluctuations (RMSFs) and measure protein stability, respectively. The results showed that docked models were more flexible and stable with TMZ, suggesting that it may be able to target putative proteins implicated in gliomagenesis that may impact radioresistance. However, additional in vitro and in vivo investigations can ascertain the potential of the selected proteins to serve as novel targets for TMZ for GBM treatment.