title: Integration of Ligand- and Target-Based Virtual Screening for the Discovery of Cruzain Inhibitors.
abstract: A myriad of methods are available for virtual screening of small organic compound databases. In this study we have successfully applied a quantitative model of consensus measurements, using a combination of 3D similarity searches (ROCS and EON), Hologram Quantitative Structure Activity Relationships (HQSAR) and docking (FRED, FlexX, Glide and AutoDock Vina), to retrieve cruzain inhibitors from collected databases. All methods were assessed individually and then combined in a Ligand-Based Virtual Screening (LBVS) and Target-Based Virtual Screening (TBVS) consensus scoring, using Receiving Operating Characteristic (ROC) curves to evaluate their performance. Three consensus strategies were used: scaled-rank-by-number, rank-by-rank and rank-by-vote, with the most thriving the scaled-rank-by-number strategy, considering that the stiff ROC curve appeared to be satisfactory in every way to indicate a higher enrichment power at early retrieval of active compounds from the database. The ligand-based method provided access to a robust and predictive HQSAR model that was developed to show superior discrimination between active and inactive compounds, which was also better than ROCS and EON procedures. Overall, the integration of fast computational techniques based on ligand and target structures resulted in a more efficient retrieval of cruzain inhibitors with desired pharmacological profiles that may be useful to advance the discovery of new trypanocidal agents.
authors.affiliation: Departamento de Química, Universidade Federal de São Carlos, 13565-905 São Carlos, SP, Brazil phone: +55 16 33739986.|Grupo de Estudos em Química Medicinal de Produtos Naturais, NEQUIMED-PN, Instituto de Química de São Carlos, Universidade de São Paulo, 13560-970 São Carlos, SP, Brazil.
authors.forename: H J
authors.initials: HJ
authors.lastname: Wiggers
authors.affiliation: Grupo de Estudos em Química Medicinal de Produtos Naturais, NEQUIMED-PN, Instituto de Química de São Carlos, Universidade de São Paulo, 13560-970 São Carlos, SP, Brazil.
authors.forename: J R
authors.initials: JR
authors.lastname: Rocha
authors.affiliation: Grupo de Estudos em Química Medicinal de Produtos Naturais, NEQUIMED-PN, Instituto de Química de São Carlos, Universidade de São Paulo, 13560-970 São Carlos, SP, Brazil.
authors.forename: J
authors.initials: J
authors.lastname: Cheleski
authors.affiliation: Departamento de Química, Universidade Federal de São Carlos, 13565-905 São Carlos, SP, Brazil phone: +55 16 33739986. montana@iqsc.usp.br.|Grupo de Estudos em Química Medicinal de Produtos Naturais, NEQUIMED-PN, Instituto de Química de São Carlos, Universidade de São Paulo, 13560-970 São Carlos, SP, Brazil. montana@iqsc.usp.br.
authors.forename: C A
authors.initials: CA
authors.lastname: Montanari
keywords: Chagas disease; Combined virtual screening; Consensus scoring; Docking; Ligand-based methodologies; QSAR; SMARTS; Similarity search