A Method for Rapid Screening of Anilide-Containing AMPK Modulators Based on Computational Docking and Biological...

Area of Science:

• Biochemistry
• Pharmacology
• Drug Discovery

Background:

• Adenosine 5'-monophosphate-activated protein kinase (AMPK) is a key regulator of cellular energy homeostasis.
• AMPK modulation is a promising therapeutic strategy for diseases including cancer, diabetes, and neurodegeneration.
• Existing AMPK activators often act indirectly, leading to potential off-target effects.

Purpose of the Study:

• To develop an efficient screening method for identifying direct AMPK modulators.
• To discover novel chemical classes of direct AMPK modulators.
• To characterize the properties and efficacy of newly identified compounds.

Main Methods:

• A hybrid approach combining in silico virtual screening and in vitro biological assays was employed.
• A large chemical library of 1,360,000 compounds was screened.
• Selected compounds underwent further biological evaluation and assessment of bioavailability using Lipinski's rule of five.

Main Results:

• A new class of direct AMPK modulators, identified as anilides or anilide-like compounds, was discovered.
• Out of 1,360,000 screened compounds, 17 were selected based on biological assays.
• 13 of the 17 selected compounds exhibited optimal bioavailability according to Lipinski's rule.
• Key structural features, including proton acceptors and hydrogen bonding interactions within the AMPK binding site, were identified as crucial for compound efficacy.

Conclusions:

• A rapid and effective screening strategy for direct AMPK modulators was successfully established.
• Anilides represent a promising new class of direct AMPK modulators.
• The identified compounds possess favorable pharmacokinetic properties and highlight the importance of specific structural interactions for AMPK modulation.