Structural activity relationship techniques

Be able to apply standard structure-activity relationship techniques to increase activity... 

Classical Quantitative Structure-Activity Relationship Techniques The early QSAR models for calcium channel ligands were based on classical Hansch analysis and elucidated the structural requirements for the binding of molecules to their receptors [111-115], It was found that various steric (Bl, L), electronic (a), and hydrophobic (n) parameters or their combination correlated well with the potency of various DHPs [111]. QSAR analysis of another set of DHPs revealed good correlations between electronic properties (F-constants) of the phenyl ring substituents and binding affinities or functional potency [112] lipophilicity as well as ortho- and meta-substituents inductivity... 

Stiefl, N. and Baumann, K. (2003) Mapping property distributions of molecular surfaces algorithm and evaluation of a novel 3D quantitative structure-activity relationship technique. J. Med. Chem.,... 

With large databases of properties, it is possible to apply QSAR (quantitative structure-activity relationship) techniques to derive good fits between molecular properties (lists exist of 1000+ properties available from ab initio calculations that can then be tested for fitabUity [2]) and the desired macroproperty. SPARC (SPARC Performs Automated Reasoning in Chemistry) is an excellent example of this approach... 

PW91 (Perdew, Wang 1991) a gradient corrected DFT method QCI (quadratic conhguration interaction) a correlated ah initio method QMC (quantum Monte Carlo) an explicitly correlated ah initio method QM/MM a technique in which orbital-based calculations and molecular mechanics calculations are combined into one calculation QSAR (quantitative structure-activity relationship) a technique for computing chemical properties, particularly as applied to biological activity QSPR (quantitative structure-property relationship) a technique for computing chemical properties... 

With the development of accurate computational methods for generating 3D conformations of chemical structures, QSAR approaches that employ 3D descriptors have been developed to address the problems of 2D QSAR techniques, that is, their inability to distinguish stereoisomers. Examples of 3D QSAR include molecular shape analysis (MSA) [26], distance geometry,and Voronoi techniques [27]. The MSA method utilizes shape descriptors and MLR analysis, whereas the other two approaches apply atomic refractivity as structural descriptor and the solution of mathematical inequalities to obtain the quantitative relationships. These methods have been applied to study structure-activity relationships of many data sets by Hopfinger and Crippen, respectively. Perhaps the most popular example of the 3D QSAR is the com-... 

Abstract Protoberberine alkaloids and related compounds represent an important class of molecules and have attracted recent attention for their various pharmacological activities. This chapter deals with the physicochemical properties of several isoquinoline alkaloids (berberine, palmatine and coralyne) and many of their derivatives under various environmental conditions. The interaction of these compounds with polymorphic DNA structures (B-form, Z-form, H -form, protonated form, triple helical form and quadruplex form) and polymorphic RNA structures (A-form, protonated form, triple helical form and quadruplex form) reported by several research groups, employing various analytical techniques such as spectrophotometry, spectrofluorimetry, circular dichro-ism, NMR spectroscopy, viscometry as well as molecular modelling and thermodynamic analysis to elucidate their mode and mechanism of action for structure-activity relationships, are also presented. 

Kosian, P.A., E.A. Makynen, P.D. Monson, D.R. Mount, A. Spacie, O.G. Mekenyan, and G.T. Ankley. 1998. Application of toxicity-based fractionation techniques and structure-activity relationship models for the identification of phototoxic polycyclic aromatic hydrocarbons in sediment pore water. Environ. Toxicol. Chem. 17 1021-1033. 

If the assignment is available or can be made in reasonable time (and preferably, but not necessarily, if the protein structure is approximately known), the location of the binding site may be easily derived. This method is currently implemented in the so-called SAR (Structure-Activity Relationship) by NMR technique [13]. 

Lipophilicity appears in several Quantitative Structure-Activity Relationships (QSAR) studies [16], emphasizing its importance. Different in vitro assays have been reported to measure lipophilicity from the classical shake-flask technique that still remains the reference for lipophilicity measurements to more actual methodologies. The first procedure is time-consuming, sensitive to impurities and the measurable log Poct range restricted to -3 to 3 [17]. 

On the other hand, factor analysis involves other manipulations of the eigen vectors and aims to gain insight into the structure of a multidimensional data set. The use of this technique was first proposed in biological structure-activity relationship (i. e., SAR) and illustrated with an analysis of the activities of 21 di-phenylaminopropanol derivatives in 11 biological tests [116-119, 289]. This method has been more commonly used to determine the intrinsic dimensionality of certain experimentally determined chemical properties which are the number of fundamental factors required to account for the variance. One of the best FA techniques is the Q-mode, which is based on grouping a multivariate data set based on the data structure defined by the similarity between samples [1, 313-316]. It is devoted exclusively to the interpretation of the inter-object relationships in a data set, rather than to the inter-variable (or covariance) relationships explored with R-mode factor analysis. The measure of similarity used is the cosine theta matrix, i. e., the matrix whose elements are the cosine of the angles between all sample pairs [1,313-316]. 

KARMA is an interactive computer assisted drug design tool that incorporates quantitative structure-activity relationships (QSAR), conformational analysis, and three-dimensional graphics. It represents a novel approach to receptor mapping analysis when the x-ray structure of the receptor site is not known, karma utilizes real time interactive three-dimensional color computer graphics combined with numerical computations and symbolic manipulation techniques from the field of artificial intelligence. 

Braumann, T. Determination of hydrophobic parameters by reversed-phase liquid chromatography theory, experimental techniques, and application in studies on quantitative structure-activity relationships, J. Chromatogr., 373 191-225, 1986. 

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