Comparison of three preprocessing filters efficiency in virtual screening: identification of new putative LXRbeta regulators as a test case.
In silico screening methodologies are widely recognized as efficient approaches in early steps of drug discovery. However, in the virtual high-throughput screening (VHTS) context, where hit compounds are searched among millions of candidates, three-dimensional comparison techniques and knowledge discovery from databases should offer a better efficiency to finding novel drug leads than those of computationally expensive molecular dockings. Therefore, the present study aims at developing a filtering methodology to efficiently eliminate unsuitable compounds in VHTS process. Several filters are evaluated in this paper. The first two are structure-based and rely on either geometrical docking or pharmacophore depiction. The third filter is ligand-based and uses knowledge-based and fingerprint similarity techniques. These filtering methods were tested with the Liver X Receptor (LXR) as a target of therapeutic interest, as LXR is a key regulator in maintaining cholesterol homeostasis. The results show that the three considered filters are complementary so that their combination should generate consistent compound lists of potential hits.
Ghemtio
Léo
L
Nancy Université, LORIA, Groupe ORPAILLEUR, Campus scientifique, BP 239, 54506 Vandoeuvre-les-Nancy Cedex, France. leo.ghemtio@loria.fr
Devignes
Marie-Dominique
MD
Smaïl-Tabbone
Malika
M
Souchet
Michel
M
Leroux
Vincent
V
Maigret
Bernard
B
D015195:Drug Design; D006801:Humans; D008024:Ligands; D000071518:Liver X Receptors; D008958:Models, Molecular; D057093:Orphan Nuclear Receptors / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding
D008024:Ligands; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors