Quantitative structure activity approaches

We recently reported a structure-activity model for variations In target organs (12) and are currently examining the possible application of the quantitative structure-activity approach to the problem of specles-to-specles differences In susceptibility toward nltrosamlne carcinogenesis (19). These two topics will be discussed In the remainder of this presentation. 

Zvinvashe, E. Murk, A. J. Rietjens, I. M. Promises and pitfalls of quantitative structure-activity approaches for predicting metabolism and toxicity, Chem. Res. Toxicol,1WI8, 21, 2229-2236. 

A challenging task in material science as well as in pharmaceutical research is to custom tailor a compound s properties. George S. Hammond stated that the most fundamental and lasting objective of synthesis is not production of new compounds, but production of properties (Norris Award Lecture, 1968). The molecular structure of an organic or inorganic compound determines its properties. Nevertheless, methods for the direct prediction of a compound s properties based on its molecular structure are usually not available (Figure 8-1). Therefore, the establishment of Quantitative Structure-Property Relationships (QSPRs) and Quantitative Structure-Activity Relationships (QSARs) uses an indirect approach in order to tackle this problem. In the first step, numerical descriptors encoding information about the molecular structure are calculated for a set of compounds. Secondly, statistical and artificial neural network models are used to predict the property or activity of interest based on these descriptors or a suitable subset. 

The QSAR (quantitative structure-activity relationship) approach has been considered for the identification of toxicants that bind to steroid and aryl... 

GR Marshall, CD Barry, HE Bosshard, RA Dammkoehler, DA Dunn. The conformational parameter m drug design The active analog approach. ACS Symp Ser 112 205-226, 1979. JL Fauchere, ed. QSAR Quantitative Structure-Activity Relationships m Drug Design. New York Alan R Liss, 1989, pp 177-181. 

S Hellberg, M Sjostrom, B Skagerberg, S Wold. Peptide quantitative structure-activity relationships, a multivariate approach. I Med Chem 30 1126-1135, 1987. 

Medicinal Chemistry Approaches and the Role of Quantitative Structure Activity Relationships... 

Smith PA, Sorich MJ, McKinnon RA, Miners JO. Pharmacophore and quantitative structure-activity relationship modeling complementary approaches for the rationalization and prediction of UDP-glucuronosyltransferase 1A4 substrate selectivity. J Med Chem 2003 46 1617-26. 

Certain computational methodologies such as some approaches to quantitative structure-activity relationship (QSAR) studies use 3D ligand structures [37, 38]. These methods generally assume that a bioactive conformation has been estab-Hshed for a set of molecules and that these conformers can be ahgned in a maimer that reflects the relative orientation they would adopt in a binding site. It is thus... 

The CHI index is reportedly a relevant parameter in quantitative structure-activity relationship (QSAR) studies [41]. With this approach, log P could be determined in the range -0.45more than 25000 compounds with excellent reproducibility (within 2 index units) and reported in a GlaxoSmithKline database [11]. Two main drawbacks were identified using this approach (i) the assumptions used in Ref [7], i.e. that S is constant for all compounds and that the system dwell volume is excluded in calculations, yield some discrepancies in the resulting log P, and (ii) the set of gradient calibration... 

Petrauskas, A. A., Kolovanov, E. A. ACD approaches for phys-chem data prediction. In 13th Eur. Symp. on Quantitative Structure-Activity Relationships, Dtisseldorf 2000, abstr. book p. 4. 

Scherrer, R. A. The treatment of ionizable compounds in quantitative structure-activity smdies with special consideration to ion partitioning. In Pesticide Synthesis Throi h Rational Approaches (ACS Symp. Ser. 255), Magee, P. S., Kohn, G. K., Menn, J. J. (eds.), American Chemical Society, Washington, DC, 1984, pp. 225-246. 

Among the possible alternative methods, in vitro assay (for ATMs) and quantitative structure-activity relationships (QSARs) models (for ANTMs) are the most applied approaches in the toxicological and ecotoxicological evaluation of chemicals profiles, even in the field of environmental research and risk assessment. 

Quantitative Structure-Activity Relationship (QSAR) Approaches... 

Quantitative Structure-Activity Relationship (QSAR) approach was first developed by Cros (1863) and Brown and Fraser (1868). In the 1960s, C. Hansch, T. Fujita, S. M. Free Jr. and J. W. Wilson started what is now considered to be classical QSAR. A series of powerful advanced computer tools have now been introduced, increasing the capacity of QSAR. 

For both nonspecific and structure-based approaches, physicochemical solvation parameters may be used directly, or they may be embedded in quantitative structure-activity relationships.3 This chapter starts with a review of the thermodynamic equations that may be used for a quantitative description of the free energy of solutes in fluid media. Then it provides an... 

Thomsen M, Dobel S, Lassen P, Carlsen L, Mogensen BB, Hansen PE (2002) Reverse quantitative structure-activity relationship for modelling the sorption of esfenvalerate to dissolved organic matter. A multivariate approach. Chemosphere 49 1317-1325... 

A hierarchical approach. In Quantitative Structure-Activity Relationship (QSAR) Models of Mutagens and Carcinogens, Benigni, R., Ed., CRC Press, Boca Raton, FL, 2003, pp. 207-234. 

Giovanni Greco, Ettore Novellino, and Yvonne Connolly Martin, Approaches to Three-Dimensional Quantitative Structure-Activity Relationships. 

De Benedetti, P.G., Menziani, M.C., Fanelli, F. and Cocchi, M. (1993) The heuristic-direct approach to quantitative structure-activity relationship analysis. Journal of Molecular Structure (Theochem), 285, 147-153. 

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