Evaluating scoring functions for docking and designing β-secretase inhibitors

COMP 24

M. Katharine Holloway1, J. Christopher Culberson1, Joseph Shpungin1, Sanjeev Munshi2, Craig A. Coburn3, Shawn J. Stachel3, Kristen G. Jones3, Elizabeth Loutzenhiser3, Alison R. Gregro3, Ming Tain Lai4, Ming Chih Crouthamel4, and Beth L. Pietrak4. (1) Molecular Systems, Merck Research Laboratories, West Point, PA 19446, (2) Structural Biology, Merck Research Laboratories, West Point, PA 19446, (3) Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19446, (4) Biological Chemistry, Merck Research Laboratories, West Point, PA 19446
β-Secretase (also known as β-APP Cleaving Enzyme or BACE-1) is one of two proteases responsible for processing the membrane-bound Amyloid Precursor Protein (APP) to the 40/42 residue β-amyloid peptide (Aβ), the primary constituent of the amyloid plaques observed in the brains of Alzheimer’s patients. Since BACE-1 cleavage of APP appears to be the rate-limiting step in the production of Aβ and BACE-1 knockout mice show complete absence of Aβ with no reported side effects, BACE-1 appears to be an attractive therapeutic target in the treatment of Alzheimer’s disease. BACE-1 has been characterized as the first known example of a pepsin-like aspartyl protease that is membrane-tethered. However, a crystal structure of the soluble domain reveals a high degree of similarity to the tertiary structures of other mammalian and fungal aspartyl proteases, e.g. renin, cathepsin D, and endothiapepsin. Given the availability of 3D coordinates for BACE-1, it appeared likely that an appropriate docking/scoring protocol could be identified which would aid in the design of BACE-1 inhibitors. Several scoring functions were evaluated based on the structures and observed activities for a small series of hydroxyethylamine inhibitors. To test the predictivity of the scoring, a virtual ‘reagent scan’ was performed to evaluate the predicted binding energy of approximately 700 amine reagents in the S1’ site. Several high-scoring amine reagents were selected for incorporation and led to potent BACE-1 inhibitors. This study demonstrates the utility of a virtual approach to selecting reagents. In addition, it supports previous qualitative conclusions about the character of the S1’ site in BACE-1 relative to other aspartyl proteases.
 

Docking and Scoring
1:30 PM-5:20 PM, Sunday, August 22, 2004 Pennsylvania Convention Center -- 109B, Oral

Division of Computers in Chemistry

The 228th ACS National Meeting, in Philadelphia, PA, August 22-26, 2004