title: Molecular features related to HIV integrase inhibition obtained from structure- and ligand-based approaches.
abstract: Among several biological targets to treat AIDS, HIV integrase is a promising enzyme that can be employed to develop new anti-HIV agents. The aim of this work is to propose a mechanistic interpretation of HIV-1 integrase inhibition and to rationalize the molecular features related to the binding affinity of studied ligands. A set of 79 HIV-1 integrase inhibitors and its relationship with biological activity are investigated employing 2D and 3D QSAR models, docking analysis and DFT studies. Analyses of docking poses and frontier molecular orbitals revealed important features on the main ligand-receptor interactions. 2D and 3D models presenting good internal consistency, predictive power and stability were obtained in all cases. Significant correlation coefficients (r(2) = 0.908 and q(2)= 0.643 for 2D model; r(2)= 0.904 and q(2)= 0.719 for 3D model) were obtained, indicating the potential of these models for untested compounds. The generated holograms and contribution maps revealed important molecular requirements to HIV-1 IN inhibition and several evidences for molecular modifications. The final models along with information resulting from molecular orbitals, 2D contribution and 3D contour maps should be useful in the design of new inhibitors with increased potency and selectivity within the chemical diversity of the data.
authors.affiliation: Instituto de Química de São Carlos, Universidade de São Paulo, São Carlos, Brazil.
authors.forename: Luciana L
authors.initials: LL
authors.lastname: de Carvalho
authors.affiliation: Centro de Ciências Naturais e Humanas, Universidade Federal do ABC, Santo André, Brazil.
authors.forename: Vinícius G
authors.initials: VG
authors.lastname: Maltarollo
authors.affiliation: Escola de Artes, Ciências e Humanidades, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Emmanuela Ferreira
authors.initials: EF
authors.lastname: de Lima
authors.affiliation: Centro de Ciências Exatas e da Natureza, Universidade Federal da Paraíba, João Pessoa, Brazil.
authors.forename: Karen C
authors.initials: KC
authors.lastname: Weber
authors.affiliation: Centro de Ciências Naturais e Humanas, Universidade Federal do ABC, Santo André, Brazil ; Escola de Artes, Ciências e Humanidades, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Kathia M
authors.initials: KM
authors.lastname: Honorio
authors.affiliation: Instituto de Química de São Carlos, Universidade de São Paulo, São Carlos, Brazil.
authors.forename: Albérico B F
authors.initials: AB
authors.lastname: da Silva
mesh_terms: D062126:Databases, Chemical; D019428:HIV Integrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008024:Ligands; D062105:Molecular Docking Simulation; D011760:Pyrrolidinones / Q000737:chemistry / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D000068898:Raltegravir Potassium; D015203:Reproducibility of Results
chemical_list: D019428:HIV Integrase Inhibitors; D008024:Ligands; D011760:Pyrrolidinones; D000068898:Raltegravir Potassium