%0 Journal Article %1 Deng2005DynamicPharmacophore %A Deng, Jinxia %A Lee, Keun Woo %A Sanchez, Tino %A Cui, Meng %A Neamati, Nouri %A Briggs, James M. %D 2005 %J Journal of Medicinal Chemistry %K drug-design dynamic-pharmacophore pharmacophore %N 5 %P 1496-1505 %R 10.1021/jm049410e %T Dynamic Receptor-Based Pharmacophore Model Development and Its Application in Designing Novel HIV-1 Integrase Inhibitors %U http://dx.doi.org/10.1021/jm049410e %V 48 %X 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 (IC50 lower than 20 μM) 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 IC50s of 8 μM and 15 μM, 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.

@article{Deng2005DynamicPharmacophore, abstract = { 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 (IC50 lower than 20 μM) 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 IC50s of 8 μM and 15 μM, 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. }, added-at = {2017-03-09T20:39:30.000+0100}, author = {Deng, Jinxia and Lee, Keun Woo and Sanchez, Tino and Cui, Meng and Neamati, Nouri and Briggs, James M.}, biburl = {https://www.bibsonomy.org/bibtex/27e64418509f67c5ea7555395c0814838/salotz}, description = {Dynamic Receptor-Based Pharmacophore Model Development and Its Application in Designing Novel HIV-1 Integrase Inhibitors - Journal of Medicinal Chemistry (ACS Publications)}, doi = {10.1021/jm049410e}, eprint = {http://dx.doi.org/10.1021/jm049410e}, interhash = {e973725ee026d3384861bf6a829e5541}, intrahash = {7e64418509f67c5ea7555395c0814838}, journal = {Journal of Medicinal Chemistry}, keywords = {drug-design dynamic-pharmacophore pharmacophore}, note = {PMID: 15743192}, number = 5, pages = {1496-1505}, timestamp = {2017-03-09T20:39:30.000+0100}, title = {Dynamic Receptor-Based Pharmacophore Model Development and Its Application in Designing Novel HIV-1 Integrase Inhibitors}, url = {http://dx.doi.org/10.1021/jm049410e}, volume = 48, year = 2005 }