Background:
Acquired Immunodeficiency Syndrome (AIDS) caused by Human Immunodeficiency
Virus (HIV) has seriously threatened human health, so development of new, selective
and safe non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) remains a high priority for
medical research. Diaryltriazine (DATA) have been identified as a new class of potent nonnucleoside
HIV-1 Reverse Transcriptase (RT) inhibitors. The study deals with Topomer CoMFA
(Comparative Molecular Field Analysis) and molecular docking to explore the important features of
DATA analogues for exerting potent HIV-1 RT inhibitors activity.
Methods:
In this work, 40 DATA analogues were studied using a combination of molecular modeling
techniques including Three-Dimensional Quantitative Structure–Activity Relationship (3D-QSAR),
molecular docking, and Topomer CoMFA were used to build 3D-QSAR models.
Results:
The results show that the Topomer CoMFA analysis has the cross-validation q2 = 0.800,
SDCV = 0.45, the non-cross-validated r2 = 0.958, SD = 0.21, and the correlation coefficient of external
validation Q2 ext = 0.965 showed that the model is reasonable and credible, and has a good predictive
ability. Then binding mode pattern of the compounds to the binding site of enzyme was
confirmed and the mechanism of drug and acceptor was studied by docking studies, the results
showed that the drug and GLU138, LYS101, THR139 sites have an obvious function, these researches
have provided an useful information for designing more effective HIV-1IN inhibitors.
Conclusion:
A series of 40 DATAs analogues was subjected to a 3D-QSAR study. Using Topomer
CoMFA 3D-QSAR method built model, and the model has shown a good predictive and statistical
validation. Substituent with low electronic density in the R5 and R3 positions and substituent with
high electronic density in the R2 and C2 positions will increase the biological activity, small substituent
on R4 positions and naphthyloxy as the spacer group C6 substituent hydrophobic will increase
biological activity. This effect is supported by Topomer CoMFA contour map and docking
results of HIV-1RT inhibition active site, the results of the 3D-QSAR and docking analyses have
provided a guide for the synthesis of new putative inhibitors for HIV-1RT to improved inhibitory
activity.
Facile Synthesis of Non-nucleoside Compounds Starting from α-Chlorocarbenium Ions and Isocyanates as Potential HIV-1 Reverse Transcriptase Inhibitors