Structural Characterization of Alpha-methylacyl-CoA Racemase: Comparative Structural Modeling, Molecular Docking and...

Area of Science:

• Biochemistry
• Structural Biology
• Drug Discovery

Background:

• Alpha-Methylacyl-CoA racemase (AMACR) is a crucial enzyme in cholesterol and fatty acid metabolism.
• AMACR is recognized as a significant biomarker for solid tumors and a potential therapeutic target.
• The three-dimensional structure of human AMACR has not yet been elucidated.

Purpose of the Study:

• To generate a homology model of the human AMACR enzyme.
• To identify potent inhibitors of AMACR through molecular docking and simulation.
• To evaluate the potential of identified inhibitors as anti-cancer drug leads.

Main Methods:

• Homology modeling using Modeller and various modeling servers with 1X74A as a template.
• Validation of the 3D model using PROCHECK, ERRAT, and ProSA energy plots.
• Molecular docking and dynamics simulations to assess enzyme-inhibitor interactions and complex stability.

Main Results:

• A validated three-dimensional homology model of human AMACR was successfully generated.
• 2-methylmyristoyl-CoA demonstrated effective binding and inhibition of AMACR via hydrogen bonds with key residues.
• Molecular dynamics simulations confirmed the high binding affinity and stability of the AMACR/2-methylmyristoyl-CoA complex.

Conclusions:

• The generated AMACR model provides a structural basis for inhibitor design.
• 2-methylmyristoyl-CoA is identified as a promising lead compound for developing novel AMACR inhibitors.
• This study supports the development of AMACR-targeted anti-cancer therapeutics.