%0 Journal Article %1 Glick2002MultiscaleLigandRepresentations %A Glick, Meir %A Grant, Guy H. %A Richards, W. Graham %D 2002 %J Journal of Medicinal Chemistry %K flexible-ligand flexible-ligand-model ligand ligand-docking ligand-modeling molecular-modeling pharmacophore %N 21 %P 4639-4646 %R 10.1021/jm020830i %T Docking of Flexible Molecules Using Multiscale Ligand Representations %U http://dx.doi.org/10.1021/jm020830i %V 45 %X Structural genomics will yield an immense number of protein three-dimensional structures in the near future. Automated theoretical methodologies are needed to exploit this information and are likely to play a pivotal role in drug discovery. Here, we present a fully automated, efficient docking methodology that does not require any a priori knowledge about the location of the binding site or function of the protein. The method relies on a multiscale concept where we deal with a hierarchy of models generated for the potential ligand. The models are created using the k-means clustering algorithm. The method was tested on seven protein−ligand complexes. In the largest complex, human immunodeficiency virus reverse transcriptase/nevirapin, the root mean square deviation value when comparing our results to the crystal structure was 0.29 Å. We demonstrate on an additional 25 protein−ligand complexes that the methodology may be applicable to high throughput docking. This work reveals three striking results. First, a ligand can be docked using a very small number of feature points. Second, when using a multiscale concept, the number of conformers that require to be generated can be significantly reduced. Third, fully flexible ligands can be treated as a small set of rigid k-means clusters.

@article{Glick2002MultiscaleLigandRepresentations, abstract = { Structural genomics will yield an immense number of protein three-dimensional structures in the near future. Automated theoretical methodologies are needed to exploit this information and are likely to play a pivotal role in drug discovery. Here, we present a fully automated, efficient docking methodology that does not require any a priori knowledge about the location of the binding site or function of the protein. The method relies on a multiscale concept where we deal with a hierarchy of models generated for the potential ligand. The models are created using the k-means clustering algorithm. The method was tested on seven protein−ligand complexes. In the largest complex, human immunodeficiency virus reverse transcriptase/nevirapin, the root mean square deviation value when comparing our results to the crystal structure was 0.29 Å. We demonstrate on an additional 25 protein−ligand complexes that the methodology may be applicable to high throughput docking. This work reveals three striking results. First, a ligand can be docked using a very small number of feature points. Second, when using a multiscale concept, the number of conformers that require to be generated can be significantly reduced. Third, fully flexible ligands can be treated as a small set of rigid k-means clusters. }, added-at = {2017-03-09T20:47:30.000+0100}, author = {Glick, Meir and Grant, Guy H. and Richards, W. Graham}, biburl = {https://www.bibsonomy.org/bibtex/23b3e837668b67ab012185d8e503c02c6/salotz}, description = {Docking of Flexible Molecules Using Multiscale Ligand Representations - Journal of Medicinal Chemistry (ACS Publications)}, doi = {10.1021/jm020830i}, eprint = {http://dx.doi.org/10.1021/jm020830i}, interhash = {c41095c02b19221430c58c827dc97db8}, intrahash = {3b3e837668b67ab012185d8e503c02c6}, journal = {Journal of Medicinal Chemistry}, keywords = {flexible-ligand flexible-ligand-model ligand ligand-docking ligand-modeling molecular-modeling pharmacophore}, note = {PMID: 12361390}, number = 21, pages = {4639-4646}, timestamp = {2017-03-09T20:47:30.000+0100}, title = {Docking of Flexible Molecules Using Multiscale Ligand Representations}, url = {http://dx.doi.org/10.1021/jm020830i}, volume = 45, year = 2002 }