Title:Structural Characterization of Alpha-methylacyl-CoA Racemase: Comparative Structural Modeling, Molecular Docking and Dynamic Simulations Studies
Volume: 15
Issue: 9
Author(s): Sumra Wajid Abbasi and Syed Sikander Azam
Affiliation:
Keywords:
Alpha-methylacyl-CoA racemase, binding free energy calculations, homo sapiens, homology modelling, molecular
docking, molecular dynamics, prostate cancer.
Abstract: α-Methylacyl-CoA racemase (AMACR) has recently been reported as a vital solid tumor
marker and is an attractive target for designing anti-tumor agents. It is a mitochondrial and
peroxisomal enzyme which plays a central role in the oxidation of cholesterol metabolites and
branched chain fatty acids. The three dimensional structure of human AMACR is still unknown. In
the current study, homology model using Modeller and different modelling servers based on 1X74A
as template is reported. The three dimensional model generated was validated and evaluated using
various available programs like PROCHECK, ERRAT, ProSA energy plots, etc. In order to find
potent inhibitors of AMACR, a docking study using compounds reported to be active against this enzyme of other
organisms was conducted. Among the studied inhibitors, 2-methylmyristoyl- CoA effectively binds to and inhibits the
enzyme by means of hydrogen bond interactions with the key residues of pocket. Moreover, molecular dynamics
simulation was carried out to check the stability of AMACR/2-methylmyristoyl-CoA complex. The results illustrated the
ligand’s high binding affinity with enzyme and the stability of hydrogen bond interactions in dynamic condition. Hence,
2-methylmyristoyl-CoA has been suggested to be a promising lead compound for the design of new inhibitors against
AMACR.
