Pharmacophore

About: Pharmacophore is a research topic. Over the lifetime, 7721 publications have been published within this topic receiving 167336 citations.

Drug Design Strategies for Targeting G‐Protein‐Coupled Receptors

Abstract: G-protein-coupled receptors (GPCRs) form a large protein family that plays an important role in many physiological and pathophysiological processes. Since the sequencing of the human genome has revealed several hundred new members of this receptor family, many new opportunities for developing novel therapeutics have emerged. The increasing knowledge of GPCRs (biological target space) and their ligands (chemical ligand space) enables novel drug design strategies to accelerate the finding and optimization of GPCR leads: The crystal structure of rhodopsin provides the first three-dimensional GPCR information, which now supports homology modeling studies and structure-based drug design approaches within the GPCR target family. On the other hand, the classical ligand-based design approaches (for example, virtual screening, pharmacophore modeling, quantitative structure-activity relationship (QSAR)) are still powerful methods for lead finding and optimization. In addition, the cross-target analysis of GPCR ligands has revealed more and more common structural motifs and three-dimensional pharmacophores. Such GPCR privileged structural motifs have been successfully used by many pharmaceutical companies to design and synthesize combinatorial libraries, which are subsequently tested against novel GPCR targets for lead finding. In the near future structural biology and chemogenomics might allow the mapping of the ligand binding to the receptor. The linking of chemical and biological spaces will aid in generating lead-finding libraries, which are tailor-made for their respective receptor.

A common pharmacophore for epothilone and taxanes: Molecular basis for drug resistance conferred by tubulin mutations in human cancer cells

Abstract: The epothilones are naturally occurring antimitotic drugs that share with the taxanes a similar mechanism of action without apparent structural similarity. Although photoaffinity labeling and electron crystallographic studies have identified the taxane-binding site on β-tubulin, similar data are not available for epothilones. To identify tubulin residues important for epothilone binding, we have isolated two epothilone-resistant human ovarian carcinoma sublines derived in a single-step selection with epothilone A or B. These epothilone-resistant sublines exhibit impaired epothilone- and taxane-driven tubulin polymerization caused by acquired β-tubulin mutations (β274Thr→Ile and β282Arg→Gln) located in the atomic model of αβ-tubulin near the taxane-binding site. Using molecular modeling, we investigated the conformational behavior of epothilone, which led to the identification of a common pharmacophore shared by taxanes and epothilones. Although two binding modes for the epothilones were predicted, one mode was identified as the preferred epothilone conformation as indicated by the activity of a potent pyridine-epothilone analogue. In addition, the structure–activity relationships of multiple taxanes and epothilones in the tubulin mutant cells can be fully explained by the model presented here, verifying its predictive value. Finally, these pharmacophore and activity data from mutant cells were used to model the tubulin binding of sarcodictyins, a distinct class of microtubule stabilizers, which in contrast to taxanes and the epothilones interact preferentially with the mutant tubulins. The unification of taxane, epothilone, and sarcodictyin chemistries in a single pharmacophore provides a framework to study drug–tubulin interactions that should assist in the rational design of agents targeting tubulin.

Pharmacophore perception, development, and use in drug design

Abstract: The book entitiled Pharmacophore Perception, Development, and Use in Drug Design, which has been just released [1], is the first monograph dedicated to the topic of the pharmacophore. It is authored by 56 experts [2] in the fields of computational chemistry and chemoand bioinformatics. The first chapter stes the tone for the volume by giving a very interesting account of the evolution of the concepts of pharmacophore and related terms such as chromophore, chemotherapy (p.6), topological patterns of molecules, drug-receptor interaction (p.7), ligand-receptor binding, topographic patterns (p.8) and so on. Below is the Table of

The binding mode of epothilone A on alpha,beta-tubulin by electron crystallography

Abstract: The structure of epothilone A, bound to alpha,beta-tubulin in zinc-stabilized sheets, was determined by a combination of electron crystallography at 2.89 angstrom resolution and nuclear magnetic resonance-based conformational analysis. The complex explains both the broad-based epothilone structure-activity relationship and the known mutational resistance profile. Comparison with Taxol shows that the longstanding expectation of a common pharmacophore is not met, because each ligand exploits the tubulin-binding pocket in a unique and independent manner.

A common reference framework for analyzing/comparing proteins and ligands. Fingerprints for Ligands and Proteins (FLAP): theory and application.

Abstract: A fast new algorithm (Fingerprints for Ligands And Proteins or FLAP) able to describe small molecules and protein structures using a common reference framework of four-point pharmacophore fingerprints and a molecular-cavity shape is described in detail. The procedure starts by using the GRID force field to calculate molecular interaction fields, which are then used to identify particular target locations where an energetic interaction with small molecular features would be very favorable. The target points thus calculated are then used by FLAP to build all possible four-point pharmacophores present in the given target site. A related approach can be applied to small molecules, using directly the GRID atom types to identify pharmacophoric features, and this complementary description of the target and ligand then leads to several novel applications. FLAP can be used for selectivity studies or similarity analyses in order to compare macromolecules without superposing them. Protein families can be compared an...