Pharmacophore Fingerprinting. 1. Application to QSAR and Focused Library Design

Abstract

A new method of rapid pharmacophore fingerprinting (PharmPrint method) has been developed. A basis set of 10,549 three-point pharmacophores has been constructed by enumerating several distance ranges and pharmacophoric features. Software has been developed to assign pharmacophoric types to atoms in chemical structures, generate multiple conformations, and construct the binary fingerprint according to the pharmacophores that result. The fingerprint is used as a descriptor for developing a quantitative structure-activity relationship (QSAR) model using partial least squares. An example is given using sets of ligands for the estrogen receptor (ER). The result is compared with previously published results on the same data to show the superiority of a full 3D, conformationally flexible approach. The QSAR model can be readily interpreted in structural/chemical terms. Further examples are given using binary activity data and some of our novel in-house compounds, which show the value of the model when crossing compound classes.

Multiple Pharmacophores for the Investigation of Human UDP-Glucuronosyltransferase Isoform Substrate Selectivity

“…There are very few methods for modeling data using multiple pharmacophores (Chen et al, 1999;McGregor and Muskal, 1999;Penzotti et al, 2002). The method described here is based around the use of clustering and a genetic algorithm to select a small number of relevant and diverse pharmacophores from a pharmacophore fingerprint.…”

“…Thus, at least for some isoforms, multiple pharmacophores may be required to model metabolism by UGT. Although algorithms for multiple pharmacophore perception exist (Chen et al, 1999;McGregor and Muskal, 1999;Penzotti et al, 2002), they are generally used for chemical database searching rather than accurate prediction of chemical properties.…”

Chemical Structure Indices in In Silico Molecular Design

“…All these approaches have variety of applications in drug research concerning to the characterization of chemical structures, diversity/ similarity analysis, selection and acquisition of compound from libraries and databases [110][111][112][113][114]. Hologram QSAR (HQSAR), a QSAR technique devoid of molecular descriptors, also uses characteristic fragment fingerprints (molecular holograms) as predictive variables of biological activity [115].…”

Towards integrated ADME prediction: past, present and future directions for modelling metabolism by UDP-glucuronosyltransferases

“…However, this assumption clearly does not hold for many drug-metabolising enzymes, which often generate multiple metabolites from a single chemical presumably due to multiple binding modes. While the field of drug-metabolism prediction is a novel application for such 'pharmacophore fingerprints', successful application of this concept has been reported in other fields of drug discovery [54,55]. Indeed multiple pharmacophores have also been utilised to characterise molecular recognition by a number of xenobiotic binding proteins [56][57][58].…”