Quantitative pharmacophore models

P. G. DeBeneditti, Theoretical Approaches to Quantitative Pharmacophore Modeling— Biological Activity Relationships, Elsevier, Amsterdam, The Netherlands, 1999. 

In Table 1, information about the origin and the characteristics of the different types of pharmacophores that can be generated is summarized. In their great majority, pharmacophore models are qualitative tools, but some methods can associate experimental activity values of the molecules in the building process to derive quantitative pharmacophore models. Examples of these are HASL, APEX, and HypoGen. Conformer generation is often a prerequisite, especially when working with flexible molecules. 

Risperidone (11) was also included among a a 1-adrenergic receptor antagonists to study a quantitative structure-activity relationship (99BMC2437). A pharmacophore model for atypical antipsychotics, including 11, was established (00MI41). An increased plasma level of 11 and 9-hydroxyrisperidone (12) was observed in combination with paroxetine (01 MI 13). The effect of vanlafaxine on the pharmacokinetics of 11 was reported (99MI13). 

These pharmacophore techniques are different in format from the traditional pharmacophore definitions. They can not be easily visualized and mapped to the molecular structures rather, they are encoded as keys or topological/topographical descriptors. Nonetheless, they capture the same idea as the classic pharmacophore concept. Furthermore, this formalism is quite useful in building quantitative predictive models that can be used to classify and predict biological activities. 

De Benedetti, P.G., Cocchi, M., Menziani, M.C. and Fanelli, F. (1993) Theoretical quantitative structure-activity analysis and pharmacophore modelling of selective non congeneric ala-adrenergic antagonists. Journal of Molecular Structure (Theochem), 280, 283-290. 

This chapter discusses the application of popular cheminfor-matics approaches, such as rigorously built QSAR models and shape pharmacophore models, to the problem of targeted library design. QSAR models offer unique ability to rationalize existing experimental SAR data in the form of robust quantitative... 

Often, all alignment-based methods and molecular field and potential calculations are classified as pharmacophore perception techniques. We will include most of these methods in this review however, when using the term pharmacophore model, we will be referring mainly to one specific type of perception, namely three-dimensional feature-based pharmacophore models represented by geometry or location constraints, qualitative or quantitative. An extrapolation of the pharmacophore approach to a set of multi-dimensional descriptors (pharmacophore fingerprints) has been developed mostly for library design and focusing purposes [3-8]. 

Over the past 60 years a multitude of means have been used to capture SARs. We can broadly divide them into two groups those based on statistical or data mining methods (e.g., regression models) and those based on physical approaches (e.g., pharmacophore models). For a comprehensive review of quantitative structure-activity relationship (QSAR) methodologies the reader is referred... 

Gupta AK, Chakroborty S, Srivastava K et al (2010) Pharmacophore modeling of substituted 1,2,4-Trioxanes for quantitative prediction of their antimalarial activity. J Chem Inf Model 50(8) 1510-1520... 

One goal of SAR studies is to put forward a pharmacophore model that can elucidate the activities of synthesized derivatives, as well as predict the activity of novel derivatives. A three-dimensional quantitative SAR study was attempted for ginkgolides and the PAF receptor, using comparative molecular field analysis and 25 ginkgolide analogs, mainly those synthesized by Corey et al. " In agreement with the SAR studies just described, this pharmacophore model predicted that substituents in the lO-OH position of GB would improve activity. 

Structure-based molecular modeling is another promising approach to improvement of the prediction of region-specificity of P450 metabolism. De Groot developed pharmacophore models and three-dimensional quantitative structure-activity relationships either alone or in combination with protein homology models to provide substrate-binding specificity information for CYP jgS. ... 

A useful pharmacophore model must be able to correctly classify - and in the case of quantitative models, correctly predict the affinity of - a so-called test or validation set, which consists of active compounds that were not used during the generation of the model. Often the ability of the model to retrieve known actives from a larger drug-like database is also assayed. It has been confirmed by several studies that the characteristics of the known inactives or decoys chosen for VS assessments have a significant impact on the enrichment of VS approaches. ... 

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