title: Integrating computational and mixture-based screening of combinatorial libraries.
abstract: Mixture-based synthetic combinatorial library (MB-SCL) screening is a well-established experimental approach for rapidly retrieving structure-activity relationships (SAR) and identifying hits. Virtual screening is also a powerful approach that is increasingly being used in drug discovery programs and has a growing number of successful applications. However, limited efforts have been made to integrate both techniques. To this end, we combined experimental data from a MB-SCL of bicyclic guanidines screened against the κ-opioid receptor and molecular similarity methods. The activity data and similarity analyses were integrated in a biometric analysis-similarity map. Such a map allows the molecules to be categorized as actives, activity cliffs, low similarity to the reference compounds, or missed hits. A compound with IC(50) = 309 nM was found in the "missed hits" region, showing that active compounds can be retrieved from a MS-SCL via computational approaches. The strategy presented in this work is general and is envisioned as a general-purpose approach that can be applied to other MB-SCLs.
authors.affiliation: Torrey Pines Institute for Molecular Studies, Port St Lucie, FL 34987, USA.
authors.forename: Austin B
authors.initials: AB
authors.lastname: Yongye
authors.forename: Clemencia
authors.initials: C
authors.lastname: Pinilla
authors.forename: Jose L
authors.initials: JL
authors.lastname: Medina-Franco
authors.forename: Marc A
authors.initials: MA
authors.lastname: Giulianotti
authors.forename: Colette T
authors.initials: CT
authors.lastname: Dooley
authors.forename: Jon R
authors.initials: JR
authors.lastname: Appel
authors.forename: Adel
authors.initials: A
authors.lastname: Nefzi
authors.forename: Thomas
authors.initials: T
authors.lastname: Scior
authors.forename: Richard A
authors.initials: RA
authors.lastname: Houghten
authors.forename: Karina
authors.initials: K
authors.lastname: Martínez-Mayorga
mesh_terms: D001643:Bridged Bicyclo Compounds / Q000737:chemistry; D003198:Computer Simulation; D016208:Databases, Factual; D006146:Guanidines / Q000737:chemistry; D057166:High-Throughput Screening Assays / Q000379:methods*; D008958:Models, Molecular; D008968:Molecular Conformation; D021281:Quantitative Structure-Activity Relationship; D017473:Receptors, Opioid, kappa / Q000737:chemistry; D054852:Small Molecule Libraries / Q000737:chemistry*
chemical_list: D001643:Bridged Bicyclo Compounds; D006146:Guanidines; D017473:Receptors, Opioid, kappa; D054852:Small Molecule Libraries