In Silico Targeting of Fascin Protein for Cancer Therapy: Benchmarking, Virtual Screening and Molecular Dynamics Approaches.
Heba H A HassanMuhammad I IsmailMohammad A S AbourehabFrank M BoecklerTamer M IbrahimReem K ArafaPublished in: Molecules (Basel, Switzerland) (2023)
Fascin is an actin-bundling protein overexpressed in various invasive metastatic carcinomas through promoting cell migration and invasion. Therefore, blocking Fascin binding sites is considered a vital target for antimetastatic drugs. This inspired us to find new Fascin binding site blockers. First, we built an active compound set by collecting reported small molecules binding to Fascin's binding site 2. Consequently, a high-quality decoys set was generated employing DEKOIS 2.0 protocol to be applied in conducting the benchmarking analysis against the selected Fascin structures. Four docking programs, MOE, AutoDock Vina, VinaXB, and PLANTS were evaluated in the benchmarking study. All tools indicated better-than-random performance reflected by their pROC-AUC values against the Fascin crystal structure (PDB: ID 6I18). Interestingly, PLANTS exhibited the best screening performance and recognized potent actives at early enrichment. Accordingly, PLANTS was utilized in the prospective virtual screening effort for repurposing FDA-approved drugs (DrugBank database) and natural products (NANPDB). Further assessment via molecular dynamics simulations for 100 ns endorsed Remdesivir (DrugBank) and NANPDB3 (NANPDB) as potential binders to Fascin binding site 2. In conclusion, this study delivers a model for implementing a customized DEKOIS 2.0 benchmark set to enhance the VS success rate against new potential targets for cancer therapies.
Keyphrases
- molecular dynamics
- molecular dynamics simulations
- cancer therapy
- crystal structure
- protein protein
- randomized controlled trial
- small cell lung cancer
- molecular docking
- squamous cell carcinoma
- public health
- density functional theory
- single cell
- drug delivery
- emergency department
- high grade
- small molecule
- cell therapy
- bone marrow
- amino acid
- climate change
- mesenchymal stem cells
- human health
- zika virus
- young adults
- mass spectrometry
- squamous cell
- drug induced
- cell migration