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    STUDIA CHEMIA - Issue no. 4 / 2010  
         
  Article:   STRUCTURE BASED ALGORITHM FOR CLASSIFICATION OF MALEIMIDE DERIVATIVES ATP-COMPETITIVE INHIBITORS OF GSK-3.

Authors:  LILIANA M. PĂCUREANU, ALINA BORA, LUMINIŢA CRIŞAN, LUDOVIC KURUNCZI.
 
       
         
  Abstract:  

The structure based retrospective virtual screening algorithm employed the docking engine FRED (Fast Rigid Exhaustive Docking) to dock 74 inhibitors (4-aryl-3-anilino-maleimide derivatives) and 1778 decoy molecules into glycogen synthase kinase-3 β, GSK-3β, ATP-binding site (PDB code 1Q4L). The input database of 74 ligands was prepared following the OpenEye protocol by adding tautomers and ionization states, generating conformers, and performing charge corrections with AM1BCC option from QUACPAC software. The protein preparation has been carried out with Chimera software by deleting water molecules (except water near Thr 138), adding hydrogen and charges (AM1BCC). The energy component values of the scoring functions were subsequently submitted to PLS-DA (Projections in Latent Structures, Discriminant Analysis). The final PLS-DA result contains only the essential energy factors that describe most accurately the interactions in the ATP binding site. The results obtained are of better quality than those obtained using the total scores provided by initial scoring functions in terms of AUC (Area Under Curve) 0.938 (chemgauss2 donor screenscore rotatable bonds) with respect to 0.887 (chemgauss3). Moreover, the early enrichment of the PLS-DA term at 1% of the database is 13.514% while for Chemgauss 3 was only 8.108%.

Keywords: molecular docking, Projections in Latent Structures - Discriminant Analysis (PLS-DA), glycogen synthase kinase-3β (GSK-3β)

 
         
     
         
         
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