Discovery, SAR, and X-ray Binding Mode Study of BCATm Inhibitors from a Novel DNA-Encoded Library

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Structural Biology

Background:

• Obesity is a complex metabolic disorder with significant health implications.
• Branched-chain amino acid aminotransferase (BCATm) is implicated in amino acid metabolism and represents a potential therapeutic target for obesity.
• Discovery of selective BCATm inhibitors is crucial for developing novel anti-obesity strategies.

Purpose of the Study:

• To identify novel inhibitors of human BCATm.
• To characterize the binding mode of identified inhibitors using structural biology techniques.
• To establish a foundation for structure-based drug discovery targeting BCATm for obesity treatment.

Main Methods:

• Screening of a large library of DNA-encoded compounds against human BCATm.
• Synthesis and activity confirmation of hit compounds, including novel libraries via on-DNA Suzuki-Miyaura cross-coupling.
• Determination of the protein crystal structure of BCATm bound to a representative inhibitor (15e).

Main Results:

• Discovery of several novel series of BCATm inhibitors.
• Identification of compound 15e with IC50 = 2.0 μM, synthesized using on-DNA Suzuki-Miyaura cross-coupling.
• Elucidation of the binding interaction of 15e within the catalytic site of BCATm, adjacent to the PLP cofactor.

Conclusions:

• The study successfully identified novel BCATm inhibitors with potential therapeutic applications for obesity.
• The determined crystal structure provides critical insights into inhibitor binding, facilitating future structure-based drug design.
• This work represents a significant starting point for the rational development of BCATm-targeted obesity therapeutics.