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.
Description
Dynamic Receptor-Based Pharmacophore Model Development and Its Application in Designing Novel HIV-1 Integrase Inhibitors - Journal of Medicinal Chemistry (ACS Publications)
%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
}