Three-dimensional pharmacophore keys

Just like structural keys, pharmacophore keys can be readily extended to account for multiple conformations. Three-point pharmacophore keys also lend themselves to visualization in the form of a three-dimensional scatter plot (see Section 5.4). A number of people have followed up Sheridan s work, most notably the groups at Chemical Design, Rhone-Poulenc, and Abbott. ... 

As is the case for structural keys, pharmacophore keys can be readily extended to account for multiple conformations. Additionally, because pharmacophores are two- and three-dimensional objects, they are able to capture information on molecular shape and chirality. Three-point pharmacophore keys also lend themselves well to visualization via three-dimensional scatter plots (see section Visualization without Dimensionality Reduction below). Sheridan s original work has been extended by a number of groups, most notably those at Chemical Design [27], Rhone-Poulenc [30], and Abbott [10]. Davies and Briant [31] have employed pharmacophore keys for similarity/diversity selection using an iterative procedure that takes into account the flexibility of the compounds and the amount of overlap between their respective keys (see section Boolean Logic). 

The understanding of three-dimensional molecular structure and the explanation of ligand-site affinity on hand of shape and functional group complementarity ( lock and key hypothesis) naturally lead to the introduction of the pharmacophore concept in medicinal chemistry and implicitly in computational chemistry see [6] and references therein. The specific physicochemical mechanisms controlling the macromolecule-ligand interactions could be, in principle, understood on a purely... 

These three pharmacophoric elements are shown as emboldened atoms within the generalized beta-blocker structure 60. The key atoms in 60 should be considered to be discretely displayed in three-dimensional (3D) space via the oxypropyl-connecting chain, so as to be able to dynamically occupy a specified residence within the beta-receptor pocket, rather than to be merely residing in a static manner on the rigid plane that becomes defined by three points. For example, reconsidering the previously noted historical development wherein a surprising enhance-... 

Pharmacophores are intrinsically three-dimensional - what, then, is topological pharmacophore supposed to mean This chapter highlights the key aspects of this topic along with some published studies. Its goal is to convey a general introduction to the main concepts and issues in 2D pharmacophore modeling, and was not conceived as an exhaustive literature review. This section briefly introduces key topics that are then detailed later on. 

Shape. Pharmacophores capture the key features of intermolecular interactions. However, they do not explicitly capture the shape and volume of the ligand, even if this is crudely implied by the largest four-point pharmacophore exhibited, and the totality of potential pharmacophores exhibited across a range of conformations encodes shape fragments. Hahn (47) has described a method for three-dimensional shape-based searching implemented in the Catalyst program. Seven... 

Complementary groups on the protein target recognize key features of the ligand. The three-dimensional arrangement of these features is commonly referred to as a pharmacophore. The Medicinal Chemistry Section of lUPAC has published a glossary of terms used in medicinal chemistry that includes an entry for the concept pharmacophore or pharmacophoric pattern. ... 

The availability of the three-dimensional structure of the protein complex allows structure-driven drug discovery approaches. In this case, a pharmacophore model is first established. This corresponds to identifying the interactions that take place at the interface and which contribute most to AG. The importance of these interactions can be validated by site-directed mutagenesis or, when possible, by the use of peptides. Once these interactions are validated, molecules containing chemical groups mimicking these key interactions are selected from compound libraries and tested. Very often these initial molecules are not optimal (e.g., they do not make all the key contacts) and they must be modified to enhance their potency. This is done, for example. 

The use of three-dimensional information for diversity analysis appears obvious, if not necessary, if one considers the origins of biological specificity. Indeed, receptors and enzymes recognize shapes and electronic properties, rather than specific substructures or atom types. This idea, which can be traced back to Fischer s lock-and-key model and Ehrlich s pharmacophore hypothesis, has had a profound impact on modem drug design, experimental and computational alike. 

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