Discovery of Small Molecule TLR4 Inhibitors as Potential Therapy for Alzheimer’s Disease

Abstract

Alzheimer’s is a potent neurodegenerative disease that causes cognitive decline. Microglia are phagocytes in the brain that can play a role in cell death and neuroinflammation, leading to Alzheimer’s. Microglia have surface receptors that activate them when ligated, and one such receptor is toll-like receptor 4 (TLR4) which this research focuses on inhibiting. By identifying compounds that obstruct the pathway between TLR4 and microglia, the neuroinflammatory response associated with microglial activation in neurodegenerative diseases will be reduced. Although experiments targeting TLR4 inhibition have been performed, this paper employs a novel approach by using a database of 20 million compounds for virtual screening to identify a suitable target compound, overcoming limitations in past studies. To execute the drug discovery process, TLR4’s binding sites were identified using a geometric, energetic, and machine-learning approach. Then, pharmacophore maps were created and virtual screening was conducted to identify 20 compounds that could inhibit TLR4. The 10 molecules with the most favorable Gibbs Free Energy were selected and their absorption and toxicity were tested. This process yielded one promising compound as a TLR4 and Alzheimer’s antagonist.