title: Ligand-Based Virtual Screening in a Search for Novel Anti-HIV-1 Chemotypes.
abstract: In a search for new anti-HIV-1 chemotypes, we developed a multistep ligand-based virtual screening (VS) protocol combining machine learning (ML) methods with the privileged structures (PS) concept. In its learning step, the VS protocol was based on HIV integrase (IN) inhibitors fetched from the ChEMBL database. The performances of various ML methods and PS weighting scheme were evaluated and applied as VS filtering criteria. Finally, a database of 1.5 million commercially available compounds was virtually screened using a multistep ligand-based cascade, and 13 selected unique structures were tested by measuring the inhibition of HIV replication in infected cells. This approach resulted in the discovery of two novel chemotypes with moderate antiretroviral activity, that, together with their topological diversity, make them good candidates as lead structures for future optimization.
authors.affiliation: Institute of Automatic Control, Silesian University of Technology , 16 Akademicka Street, 44-100 Gliwice, Poland.|Institute of Chemistry, University of Silesia , 9 Szkolna Street, 40-006 Katowice, Poland.
authors.forename: Agata
authors.initials: A
authors.lastname: Kurczyk
authors.affiliation: Institute of Pharmacology, Polish Academy of Sciences , 12 Smetna Street, 31-343 Kraków, Poland.
authors.forename: Dawid
authors.initials: D
authors.lastname: Warszycki
authors.affiliation: Institute of Chemistry, University of Silesia , 9 Szkolna Street, 40-006 Katowice, Poland.
authors.forename: Robert
authors.initials: R
authors.lastname: Musiol
authors.affiliation: Institute of Pharmacology, Polish Academy of Sciences , 12 Smetna Street, 31-343 Kraków, Poland.
authors.forename: Rafał
authors.initials: R
authors.lastname: Kafel
authors.affiliation: Institute of Pharmacology, Polish Academy of Sciences , 12 Smetna Street, 31-343 Kraków, Poland.
authors.forename: Andrzej J
authors.initials: AJ
authors.lastname: Bojarski
authors.affiliation: Institute of Chemistry, University of Silesia , 9 Szkolna Street, 40-006 Katowice, Poland.
authors.forename: Jaroslaw
authors.initials: J
authors.lastname: Polanski
mesh_terms: D019380:Anti-HIV Agents / Q000032:analysis / Q000737:chemistry*; D001681:Biological Assay; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D019428:HIV Integrase Inhibitors / Q000737:chemistry*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D000069550:Machine Learning; D008958:Models, Molecular; D015394:Molecular Structure
chemical_list: D019380:Anti-HIV Agents; D019428:HIV Integrase Inhibitors; D008024:Ligands