Identification of potential Akt activators: a ligand and structure-based computational approach

Area of Science:

• Biochemistry and Molecular Biology
• Medicinal Chemistry
• Computational Drug Discovery

Background:

• The Akt pathway is crucial in diseases such as Alzheimer's, Parkinson's, and diabetes.
• Akt phosphorylation regulates numerous downstream cellular processes.
• Small molecules binding to Akt's PH domain can enhance its activity.

Purpose of the Study:

• To identify novel small molecules that activate the Akt pathway.
• To explore structure-activity relationships of potential Akt activators.

Main Methods:

• Ligand-based virtual screening (2D QSAR, shape, pharmacophore screening).
• Structure-based drug design (docking, MM-GBSA, ADME prediction, MD simulations).
• Analysis of Akt1 PH domain (PDB: 1UNQ) interactions.

Main Results:

• Twenty-five compounds showed activity in 2D QSAR models and proceeded to screening.
• Five compounds (197105, 261126, 253878, 256085, 123435) were selected based on docking and stability.
• MD simulations identified compounds 83824832 and 12289533 as stable Akt activators with key residue interactions.

Conclusions:

• Computational approaches successfully identified potential Akt pathway activators.
• Compounds 83824832 and 12289533 demonstrate promising characteristics for further drug development.
• The identified molecules may serve as therapeutic leads for Akt-related diseases.