title: Scaffold hopping through virtual screening using 2D and 3D similarity descriptors: ranking, voting, and consensus scoring.
abstract: The ability to find novel bioactive scaffolds in compound similarity-based virtual screening experiments has been studied comparing Tanimoto-based, ranking-based, voting, and consensus scoring protocols. Ligand sets for seven well-known drug targets (CDK2, COX2, estrogen receptor, neuraminidase, HIV-1 protease, p38 MAP kinase, thrombin) have been assembled such that each ligand represents its own unique chemotype, thus ensuring that each similarity recognition event between ligands constitutes a scaffold hopping event. In a series of virtual screening studies involving 9969 MDDR compounds as negative controls it has been found that atom pair descriptors and 3D pharmacophore fingerprints combined with ranking, voting, and consensus scoring strategies perform well in finding novel bioactive scaffolds. In addition, often superior performance has been observed for similarity-based virtual screening compared to structure-based methods. This finding suggests that information about a target obtained from known bioactive ligands is as valuable as knowledge of the target structures for identifying novel bioactive scaffolds through virtual screening.
authors.affiliation: Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, P.O. Box 368, Ridgefield, Connecticut 06877-0368, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.forename: Ingo
authors.initials: I
authors.lastname: Muegge
mesh_terms: D051357:Cyclin-Dependent Kinase 2 / Q000737:chemistry; D051546:Cyclooxygenase 2 / Q000737:chemistry; D016333:HIV Protease / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D009439:Neuraminidase / Q000737:chemistry; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship; D011960:Receptors, Estrogen / Q000737:chemistry; D013917:Thrombin / Q000737:chemistry; D048051:p38 Mitogen-Activated Protein Kinases / Q000737:chemistry
chemical_list: D008024:Ligands; D011506:Proteins; D011960:Receptors, Estrogen; D051546:Cyclooxygenase 2; D051357:Cyclin-Dependent Kinase 2; D048051:p38 Mitogen-Activated Protein Kinases; D009439:Neuraminidase; D013917:Thrombin; D016333:HIV Protease