Dynamic receptor-based pharmacophore model development and its application in designing novel HIV-1 integrase inhibitors.
We present here a dynamic receptor-based pharmacophore model representing the complementary features of the active site region of HIV-1 integrase (IN), which was developed from a series of representative conformations of IN. Conformations of IN were sampled through a molecular dynamics study of the catalytic domain of an IN monomer, and an ensemble of representative IN structures were collected via a probability-based representative conformer sampling method that considers both the potential energy and the structural similarity of the protein conformations. The dynamic pharmacophore model was validated by a set of 128 known inhibitors, and the results showed that over 72% of the active inhibitors (IC(50) lower than 20 microM) could be successfully identified by the dynamic model. Therefore, we screened our in-house database of commercially available compounds against this model and successfully identified a set of structurally novel IN inhibitors. Compounds 7 and 18 with IC(50)s of 8 microM and 15 microM, respectively, against the strand transfer reaction were the most potent. Moreover, 7, 8 and 20 showed a 5-fold selectivity for the strand transfer reaction over 3'-processing.
Deng
Jinxia
J
Department of Chemical Engineering, University of Houston, Houston, TX 77204-4004, USA.
Lee
Keun Woo
KW
Sanchez
Tino
T
Cui
Meng
M
Neamati
Nouri
N
Briggs
James M
JM
D001665:Binding Sites; D020134:Catalytic Domain; D015195:Drug Design; D019427:HIV Integrase / Q000737:chemistry* / Q000235:genetics; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D008958:Models, Molecular; D008968:Molecular Conformation; D009154:Mutation; D011336:Probability; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship; D013816:Thermodynamics
D019428:HIV Integrase Inhibitors; D019427:HIV Integrase