Structure-Based Approaches to Improving Selectivity through Utilizing Explicit Water Molecules: Discovery of...

Area of Science:

• Medicinal Chemistry
• Neuroscience
• Drug Discovery

Background:

• Beta-secretase 1 (BACE1) is a key therapeutic target for Alzheimer's disease.
• BACE2 shares high homology with BACE1, complicating the development of selective inhibitors.
• Nonselective inhibition of BACE2 may lead to adverse effects due to its diverse physiological roles.

Purpose of the Study:

• To design and synthesize highly selective BACE1 inhibitors.
• To overcome the challenge posed by BACE2's structural similarity to BACE1.
• To explore structure-activity relationships for improved inhibitor selectivity.

Main Methods:

• Structure-based drug design utilizing crystallographic data of BACE1 and inhibitors.
• Identification and targeting of explicit water molecules within the enzyme's active site.
• Iterative optimization of lead compounds to enhance selectivity and potency.

Main Results:

• Propynyl oxazine derivative 3 demonstrated improved selectivity for BACE1 over BACE2.
• Compound 6 was identified as a highly selective BACE1 inhibitor.
• Cocrystal structures revealed that the propynyl group displaces a specific water molecule, contributing to selectivity.

Conclusions:

• Targeting explicit water molecules in the BACE1 active site is a viable strategy for achieving high selectivity.
• The displacement of specific water molecules by inhibitor substituents can differentiate between BACE1 and BACE2.
• This approach offers a promising path for developing safer and more effective Alzheimer's disease therapeutics.