Exploring binding mode for styrylquinoline HIV-1 integrase inhibitors using comparative molecular field analysis and docking studies.
OBJECTIVE
To understand pharmacophore properties of styrylquinoline derivatives and to design inhibitors of HIV-1 integrase.


METHODS
Comparative molecular field analysis (CoMFA) was performed to analyze three-dimensional quantitative structure-activity relationship (3D-QSAR) of styrylquinoline derivatives. Thirty-eight compounds were randomly divided into a training set of 28 compounds and a test set of 10 compounds. The stability of 3D-QSAR models was proved by the analysis of cross-validated and non-cross-validated methods. Moreover, the binding mode of these compounds and integrase was constructed by AutoDock program.


RESULTS
The CoMFA model of the training compounds was reasonably predicted with cross-validated coefficient (q2) and conventional (r2) values (up to 0.696 and 0.754). Then the model was validated by the test set. The resulting CoMFA maps visualized structural requirements for the biological activity of these inhibitors. Docking results showed that a carboxyl group at C-7 and a hydroxyl group at C-8 in the quinoline subunit, bound closely to the divalent metal cofactor (Mg2+) around the integrase catalytic site. Moreover, there is a linear correlation between the binding energy of the inhibitors with integrase and their inhibitory effect.


CONCLUSIONS
The present study indicated that the CoMFA model together with docking results could give us helpful hints for drug design as well as interpretation of the binding affinity between these inhibitors and integrase.
Ma
Xiao-hui
XH
College of Life Science and Bioengineering, Beijing University of Technology, Beijing 100022, China.
Zhang
Xiao-yi
XY
Tan
Jian-jun
JJ
Chen
Wei-zu
WZ
Wang
Cun-xin
CX
D001665:Binding Sites; D015195:Drug Design; D019427:HIV Integrase / Q000737:chemistry*; D019428:HIV Integrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D015497:HIV-1; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D011804:Quinolines / Q000737:chemistry* / Q000494:pharmacology
D019428:HIV Integrase Inhibitors; D011804:Quinolines; C481600:styrylquinoline; D019427:HIV Integrase