       Document 0330
 DOCN  M9610330
 TI    Quantitative structural activity relationship study of
       bis-tetraazacyclic compounds. A novel series of HIV-1 and HIV-2
       inhibitors.
 DT    9601
 AU    Joao HC; De Vreese K; Pauwels R; De Clercq E; Henson GW; Bridger GJ;
       Sandoz Research Institute, Vienna, Austria.
 SO    J Med Chem. 1995 Sep 15;38(19):3865-73. Unique Identifier : AIDSLINE
       MED/96009810
 AB    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.
 DE    Antiviral Agents/*CHEMISTRY/CHEMICAL SYNTHESIS/*PHARMACOLOGY  Computer
       Simulation  Drug Design  Giant Cells  Heterocyclic
       Compounds/*CHEMISTRY/CHEMICAL SYNTHESIS/  *PHARMACOLOGY  Human  HIV
       Envelope Protein gp120/METABOLISM  HIV-1/*DRUG EFFECTS/PHYSIOLOGY
       HIV-2/*DRUG EFFECTS/PHYSIOLOGY  Least-Squares Analysis  Models, Chemical
       Molecular Conformation  Molecular Structure  Software
       Structure-Activity Relationship  Virus Replication/DRUG EFFECTS  JOURNAL
       ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).

