title: Quantitative structural activity relationship study of bis-tetraazacyclic compounds. A novel series of HIV-1 and HIV-2 inhibitors.
abstract: This work describes a study of quantitative structural activity relationships (QSAR) of bis-tetraazamacrocyclic compounds. These compounds represent a novel class of very potent and selective anti-HIV inhibitors, with a new mode of action. The QSAR study correlates structural features of the compounds with anti-HIV activity, resulting in a model which has a high predictive capacity (predictive r2 = 0.79). This predictive model will be of major importance for the design of new anti-HIV inhibitors of this class. Use is made of partial least-squares (PLS) analysis, with the novelty being that structural features derived by inclusion of all sterically allowed conformations for each molecule are included in the analysis. PLS analysis was made of descriptors, including structural parameters, macrocyclic ring size, metal chelating ability, etc., and those features necessary for the observed antiviral activities of these compounds were deduced from the models. Since all sterically allowed conformations are included in the analysis, the flexibility of the molecules is also taken into account. In addition, a correlation is found (indicated by a predictive r2 value of 0.61) between inhibition of HIV-1 (HIV-2) and syncytium formation inhibition in the presence of bis-cyclam analogues, leading to the suggestion of a common target, namely, gp120, being involved in both inhibition of virus replication and syncytium formation.
authors.affiliation: Sandoz Research Institute, Vienna, Austria.
authors.forename: H C
authors.initials: HC
authors.lastname: Joao
authors.forename: K
authors.initials: K
authors.lastname: De Vreese
authors.forename: R
authors.initials: R
authors.lastname: Pauwels
authors.forename: E
authors.initials: E
authors.lastname: De Clercq
authors.forename: G W
authors.initials: GW
authors.lastname: Henson
authors.forename: G J
authors.initials: GJ
authors.lastname: Bridger
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001596:Benzylamines; D003198:Computer Simulation; D000080027:Cyclams; D015195:Drug Design; D015726:Giant Cells; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D015498:HIV-2 / Q000187:drug effects* / Q000502:physiology; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D016018:Least-Squares Analysis; D008956:Models, Chemical; D008968:Molecular Conformation; D015394:Molecular Structure; D012984:Software; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D001596:Benzylamines; D000080027:Cyclams; D015699:HIV Envelope Protein gp120; D006571:Heterocyclic Compounds; C088327:plerixafor