Background:
S-dihydro-alkyloxy-benzyl-oxopyrimidines (S-DABOs) as non-nucleoside
reverse transcriptase inhibitors have received considerable attention during the last decade due to
their high potency against HIV-1.
Methods:
In this study, three-dimensional quantitative structure-activity relationship (3D-QSAR) of
a series of 38 S-DABO analogues developed in our lab was studied using Comparative Molecular
Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA). The
Docking/MMFF94s computational protocol based on the co-crystallized complex (PDB ID: 1RT2)
was used to determine the most probable binding mode and to obtain reliable conformations for
molecular alignment. Statistically significant CoMFA (q2=0.766 and r2=0.949) and CoMSIA
(q2=0.827 and r2=0.974) models were generated using the training set of 30 compounds on the basis
of hybrid docking-based and ligand-based alignment.
Results:
The predictive ability of CoMFA and CoMSIA models was further validated using a test
set of eight compounds with predictive r2
pred values of 0.843 and 0.723, respectively.
Conclusion:
The information obtained from the 3D contour maps can be used in designing new SDABO
derivatives with improved HIV-1 inhibitory activity.
