ABSTRACT
In this review, the evolution of QSAR is traced from the insightful observations of Crum-Brown and Frazier to Hammett's critical equations and finally Hansch's seminal contributions on hydrophobicity and modelling of biological activity based on extrathermodynamic principles. Today's QSAR models can stand alone, augment other graphical approaches or be examined in tandem with equations of a similar mechanistic genre to truly reveal the power of the paradigm. This review will focus on the three standard classifications routinely used in QSAR analysis electronic, hydrophobic, and steric, as well as topological indices. Electronic parameters will focus on Hammett sigma constants and their numerous variations. Dipole moments, hydrogen bond descriptors and quantum chemical indices as well as applications of their utilization will be described. The hydrophobicity parameter will be examined by tracing its early history, its operational definition and its determination by either experimental methods or computational calculations. Steric parameters, which run the gamut from size to shape, will be described by Taft's, Hancock's, Charton's, Fujita's, Verloop's and Simon's contributions. Topological effects, delineated by connectivity indices, kappa shape and electrotopological indices of Kier and Hall are also described. Examples of QSAR models incorporating most of these parameters are reviewed. In cases where the 95% confidence intervals of variables are available, they are listed in parentheses. A brief Comparative QSAR analysis of non-nucleoside reverse transcriptase inhibitors (NNRTI's) is outlined and various models obtained by different groups examining 4, 5, 6, 7-tetrahydro-5-methylimidazo [4, 5,1-j,k][1,4] benzodiazepin-2(1H)-ones (TIBO) and 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)-thymine (HEPT) derivatives are compared for mechanistic insight that could be useful in the process of inhibitor design.
Subject(s)
Quantitative Structure-Activity Relationship , Drug Stability , Humans , Models, Chemical , Models, MolecularABSTRACT
A Fujita-Ban type analysis has been made on a few series of HIV-1 (human immunodeficiency virus of type 1) protease inhibitors and the activity contributions of various substituents obtained. From these activity contributions, a compound is predicted that may have better activity than ritonavir, presently prescribed for the treatment of patients suffering from HIV-1. A few other compounds are also suggested.
Subject(s)
HIV Protease Inhibitors/chemistry , HIV Protease Inhibitors/pharmacology , HIV-1/drug effects , Pyridines/chemistry , Pyridines/pharmacology , Ritonavir/analogs & derivatives , Animals , Cell Line , Cell Survival , Drug Design , HIV Infections/drug therapy , HIV Protease/metabolism , HIV-1/enzymology , Humans , Models, Chemical , Molecular Structure , Quantitative Structure-Activity Relationship , Ritonavir/chemistry , Ritonavir/pharmacology , Ritonavir/therapeutic use , T-Lymphocytes/drug effectsABSTRACT
QSAR have been formulated for variations of TNP-470 and Ovalicin on various cell lines. In the examples of mouse lymphocyte cells and bovine endothelial cells the results suggest an allosteric interaction. These results are compared with the binding of nitrobenzene to hemoglobin in rats in vivo. Such a reaction does not occur with methionine aminopeptidase.
Subject(s)
Angiogenesis Inhibitors/chemistry , Angiogenesis Inhibitors/pharmacology , Quantitative Structure-Activity Relationship , Sesquiterpenes/pharmacology , Aminopeptidases/antagonists & inhibitors , Animals , Cattle , Cell Division/drug effects , Cells, Cultured , Cyclohexanes , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , Inhibitory Concentration 50 , Lymphocytes/drug effects , Metalloendopeptidases/antagonists & inhibitors , Mice , O-(Chloroacetylcarbamoyl)fumagillol , Sesquiterpenes/chemistryABSTRACT
QSAR have been developed for the anticancer activity (growth inhibition) of various tumor cells by bis(11-oxo-11H-indeno[1,2-b]quinoline-6-carboxamides), bis(phenazine-1-carboxamides), and bis(naphthalimides). Of the seven QSAR, positive hydrophobic interactions are found in only two examples: bis(naphthalimides) versus human colon cancer cells. This is consistent with other QSAR of anticancer compounds where hydrophobic interactions are found to be unimportant.
Subject(s)
Antineoplastic Agents/chemistry , Quantitative Structure-Activity Relationship , 1-Naphthylamine/analogs & derivatives , 1-Naphthylamine/chemistry , Animals , Cell Division/drug effects , Dimerization , Drug Screening Assays, Antitumor , Humans , Imides/chemistry , Indenes/chemistry , Inhibitory Concentration 50 , Mice , Phenazines/chemistry , Quinolines/chemistry , Quinolones/chemistry , Tumor Cells, Cultured/drug effectsABSTRACT
Terbenzimidazoles that inhibit topoisomerase are of interest as anticancer drugs. We have reviewed the literature and have developed 13 quantitative structure-activity relationships (QSARs) on cleaving DNA or inhibiting the growth of tumor cell cultures. The results are correlated with octanol/water partition coefficients or molecular refractivity. Suggestions have been made for the development of improved derivatives.
