title: 3D virtual screening of large combinatorial spaces.
abstract: A new method for 3D in silico screening of large virtual combinatorial chemistry spaces is described. The software PharmShape screens millions of individual compounds applying a multi-conformational pharmacophore and shape based approach. Its extension, PharmShapeCC, is capable of screening trillions of compounds from tens of thousands of combinatorial libraries. Key elements of PharmShape and PharmShapeCC are customizable pharmacophore features, a composite inclusion sphere, library core intermediate clustering, and the determination of combinatorial library consensus orientations that allow for orthogonal enumeration of libraries. The performance of the software is illustrated by the prospective identification of a novel CXCR5 antagonist and examples of finding novel chemotypes from synthesizing and evaluating combinatorial hit libraries identified from PharmShapeCC screens for CCR1, LTA4 hydrolase, and MMP-13.
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Department of Medicinal Chemistry, 900 Ridgebury Road, Ridgefield, CT 06877-0368, USA. Electronic address: ingo.mugge@boehringer-ingelheim.com.
authors.forename: Ingo
authors.initials: I
authors.lastname: Muegge
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Department of Medicinal Chemistry, 900 Ridgebury Road, Ridgefield, CT 06877-0368, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
mesh_terms: D003198:Computer Simulation; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004851:Epoxide Hydrolases / Q000737:chemistry; D053509:Matrix Metalloproteinase 13 / Q000737:chemistry; D008958:Models, Molecular; D054389:Receptors, CCR1 / Q000737:chemistry; D054380:Receptors, CXCR5 / Q000737:chemistry; D012984:Software
chemical_list: D054389:Receptors, CCR1; D054380:Receptors, CXCR5; D004851:Epoxide Hydrolases; D053509:Matrix Metalloproteinase 13; C043134:leukotriene A4 hydrolase
keywords: Combinatorial library; Pharmacophore; Scoring; Shape