A novel class of small molecule Alpha, Beta-ABAD interaction inhibitors for the treatment of Alzheimer's Disease.
To learn more about the technology a published white paper (pdf) is available for download.
Quantitative structure - activity relationship (QSAR) analysis helped design these novel and reactive Alpha, Beta-ABAD inhibitors by predicting physicochemical properties to increase selectivity and affinity. Dr. Yan applied 3D QSAR methods to evaluate the molecular property fields between five known Alpha, Beta-ABAD inhibitors and 20 candidate novel compounds. The compounds with satisfactory properties were tested via molecular docking against ABAD to find out whether they are able to bind to the protein and inhibit Alpha, Beta-ABAD interaction. Benzothiazoleurea and frentizole analogues demonstrated remarkably superior permeation across biological membranes and oral bioavailability, in addition to a 30x increase in potency and reduced drug-drug interaction. In the end, 14 of the 20 compounds demonstrated high potency with attractive drug-like properties.
In quantitative structure-activity relationship and pharmacokinetic tests, Dr. Yan's compounds inhibited Alpha, Beta-ABAD interaction with high specificity and demonstrated attractive drug-like properties - including absorption, toxicity, blood brain barrier penetration, and potency - superior to those of known Alpha, Beta-ABAD interaction inhibitors.
Moreover, a molecular docking study of these novel compounds showed better interaction with the binding site - suggesting that they are safer and more effective drugs for treating AD.
Known inhibitors of Alpha, Beta-ABAD interaction have several disadvantages including low solubility, inability to cross the blood brain barrier (BBB), high toxicity, and/or low cell permeability. Efforts to design better Alpha, Beta-ABAD inhibitors have been unsuccessful due to poor ADME (absorption, distribution, metabolism and excretion) properties.