3D-SAR

D-QSAR = three-dimensional quantitative structure-activity relationship 3D-SAR = three-dimensional structure-activity relationship CoMFA = comparative molecular fields analysis DG = distance geometry HASL = hypothetical active-site lattice MLR = multiple linear regression MSA = molecular shape analysis PLS = partial least-squares. 

The aim of this article is to provide an overview of the range of methodologies that can be used to build qualitative and quantitative models of DNA or RNA-ligand interactions. The construction of such models may resort to computational methods that go beyond 3D-SAR and 3E>-QSAR, and recent reviews of these techniques are available (see Free Energy Calculations Methods and Applications Free Energy Per-turbation Calculations Free Energy Simulations and Solvation Modeling). ... 

D-QSAR from Combined 3D-SAR/Moiecular Modeling Studies... 

To establish the structure-activity relationships (SARs) of a set of molecules, a knowledge of the 3D structure is of great importance [2]. Thevand et al. recently (2004) reported the 3D structural analysis of tetrandrine using NMR and molecular modeling (the structure is shown in Fig. 1) [2]. They employed... 

HCV 3D polymerase NS5B SARS Coronavirus main protease A1-antitrypsin aggregation... 

Basak, S. C., Natarajan, R., Nowak, W., Miszta, P., Klun, J. A. Three dimensional structure-activity relationships (3D-QSAR) for insect repellency of diastereoisomeric compounds A hierarchical molecular overlay approach. SAR QSAR Environ. Res. 2007,18, 237-250. 

The quantitative comparison of the optimized 3D structure of a selected set of ligands allows the development of their minimal 3D structural requirements for the recognition and activation of the biological target, that is, the pharmacophore hypothesis, and gives a sound 3D rationale to the available SARs [21]. A more complete and mechanistically relevant approach to the development of the 3D pharmacophore consists in its translation into a numerical molecular descriptor that quantifies the molecular-pharmacophore similarity-diversity for computational QSAR modeling [21,41]. 

In the absence of crystallographic or NMR data, predictive techniques based on protein primary sequences can be used to elaborate crude 3D models. Such models will suggest that certain amino acid residues are involved in forming the active (receptor) site. The assignment of structural or functional roles to particular residues can be tested by site-directed mutagenesis, and the model can be further refined by consideration of SAR among ligands. 

Although the NMR-derived bioactive conformation of EpoA is consistent with a large number of SAR data, it does not solve the question of the orientation of the ligand in the protein binding site. One approach to overcome the lack of the 3D... 

The earliest discussion of a common pharmacophore in the tubulin literature was presented by Winkler and Axelsen [70], who employed the second strategy of simultaneous alignment while fitting only three points of S AR. Without a published 3D reference, we were not able to test their hypothesis. However, as pointed out by others [71], the predictions made based upon this earliest model were not supported by subsequent SAR studies. 

The first attempt to provide a common pharmacophore for taxanes and epothilones was made by Winkler and Axelsen [111] in 1996. Due to the complete lack of information about the SAR of epothilones recently discovered at that time, common portions were identified by search for steric and chemical similarity in the 3D conformational space of the two molecular classes. The resulting pharmacophore (Chart 15) proposed the following common regions between taxanes and epothilones. The C-2 benzoyl ring was superposed to the C-8-C-12 segment of epothilones the C-13 side chain corresponded to the C-l-C-6 segment of epothilones the C-10... 

Todeschini, R. and Gramatica, P., The WHIM theory new 3D molecular descriptors for QSAR in environmental modelling, SAR QSAR Environ. Res., 7, 89-115, 1997a. 

A set of inhibitors of the coagulation factor Xa is found to present prototypic continuous SARs. There is detectable correlation between 2D and 3D molecular similarity and most similar 2D structures bind very similarly and with... 

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