title: Docking and 3-D QSAR studies on indolyl aryl sulfones. Binding mode exploration at the HIV-1 reverse transcriptase non-nucleoside binding site and design of highly active N-(2-hydroxyethyl)carboxamide and N-(2-hydroxyethyl)carbohydrazide derivatives.
abstract: Three-dimensional quantitative structure-activity relationship (3-D QSAR) studies and docking simulations were developed on indolyl aryl sulfones (IASs), a class of novel HIV-1 non-nucleoside reverse transcriptase (RT) inhibitors (Silvestri, et al. J. Med. Chem. 2003, 46, 2482-2493) highly active against wild type and some clinically relevant resistant strains (Y181C, the double mutant K103N-Y181C, and the K103R-V179D-P225H strain, highly resistant to efavirenz). Predictive 3-D QSAR models using the combination of GRID and GOLPE programs were obtained using a receptor-based alignment by means of docking IASs into the non-nucleoside binding site (NNBS) of RT. The derived 3-D QSAR models showed conventional correlation (r(2)) and cross-validated (q(2)) coefficients values ranging from 0.79 to 0.93 and from 0.59 to 0.84, respectively. All described models were validated by an external test set compiled from previously reported pyrryl aryl sulfones (Artico, et al. J. Med. Chem. 1996, 39, 522-530). The most predictive 3-D QSAR model was then used to predict the activity of novel untested IASs. The synthesis of six designed derivatives (prediction set) allowed disclosure of new IASs endowed with high anti-HIV-1 activities.
authors.affiliation: Dipartimento di Studi di Chimica e Tecnologia delle Sostanze Biologicamente Attive, Università di Roma La Sapienza, Piazzale Aldo Moro 5, I-00185 Roma, Italy.
authors.forename: Rino
authors.initials: R
authors.lastname: Ragno
authors.forename: Marino
authors.initials: M
authors.lastname: Artico
authors.forename: Gabriella
authors.initials: G
authors.lastname: De Martino
authors.forename: Giuseppe
authors.initials: G
authors.lastname: La Regina
authors.forename: Antonio
authors.initials: A
authors.lastname: Coluccia
authors.forename: Alessandra
authors.initials: A
authors.lastname: Di Pasquali
authors.forename: Romano
authors.initials: R
authors.lastname: Silvestri
mesh_terms: D001665:Binding Sites; D002478:Cells, Cultured; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006834:Hydrazines / Q000737:chemistry; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D009705:Nucleosides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D012984:Software; D013450:Sulfones / Q000737:chemistry
chemical_list: D006834:Hydrazines; D009705:Nucleosides; D018894:Reverse Transcriptase Inhibitors; D013450:Sulfones; D054303:HIV Reverse Transcriptase; C019289:carbohydrazide