In-silico Drug Design and in-silico Screening (Track)


Afaf AL Nadaf

Medicinal Chemistry & Drug Discovery, Pharmaceutical Chemistry & Pharmacognosy, Department Pharmacy School, Applied Science University, amman-jordan


Background: Alzheimer’s disease (AD) is a degenerative disease of the brain and the most common form of dementia. A variety of therapeutic strategies for modulating the progression or prevention of AD are currently being investigated. The etiology of the disease is characterized by aggregates of amyloid plaques, largely composed of amyloid-β peptide formed from the amyloid precursor protein cleaved by β-secretase. β-secretase is a membrane-bound aspartic protease, which has become known as an important but difficult protein target.

Method: Molecular docking study using LigandFit Docking and Scoring  as well as LibDock Docking functions were performed as a preliminary in-silico screening test using binding pocket of BACE (PDB code: 2IQG) resolution:1.7 Å.  Followed  by in-vitro enzyme inhibition assay for National Cancer Institute (NCI) database. NCI compounds in there un-ionized forms were docked into the binding site; high-ranking docked conformers and poses were scored using seven scoring functions. The validation for our docking–scoring procedure was performed through employing the same conditions to dock a well-known BACE inhibitor F2I. High ranking compounds were evaluated in vitro using BACE fluorescence resonance energy transfer (FRET) assay.

Results: The docking simulation resulted in a close model to the crystallographic structure. Five of the important interactions are shared between the co-crystallized ligand and in silico hits.

Virtual screening identified low micromolar inhibitory leads from the NCI list of compounds. The most potent hit exhibited BACE IC50 values of 11.1 mM in BACE enzymatic assay.

Conclusion: We have identified a low micro-molar BACE inhibitor with IC50 of 11.1 mM. Our results suggest that in silico high-throughput screening approach can serve as usefull source to identify new hits which can be used as lead candidate for synthetic modification in order to reach more potent enzyme inhibitors.