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Pharmacophore

About: Pharmacophore is a(n) research topic. Over the lifetime, 7721 publication(s) have been published within this topic receiving 167336 citation(s).

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Journal ArticleDOI
16 Oct 1997-Nature
TL;DR: The crystal structures of the LBD of ER in complex with the endogenous oestrogen, 17β-oestradiol, and the selective antagonist raloxifene provide a molecular basis for the distinctive pharmacophore of the ER and its catholic binding properties.

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Abstract: Oestrogens are involved in the growth, development and homeostasis of a number of tissues. The physiological effects of these steroids are mediated by a ligand-inducible nuclear transcription factor, the oestrogen receptor (ER). Hormone binding to the ligand-binding domain (LBD) of the ER initiates a series of molecular events culminating in the activation or repression of target genes. Transcriptional regulation arises from the direct interaction of the ER with components of the cellular transcription machinery. Here we report the crystal structures of the LBD of ER in complex with the endogenous oestrogen, 17beta-oestradiol, and the selective antagonist raloxifene, at resolutions of 3.1 and 2.6 A, respectively. The structures provide a molecular basis for the distinctive pharmacophore of the ER and its catholic binding properties. Agonist and antagonist bind at the same site within the core of the LBD but demonstrate different binding modes. In addition, each class of ligand induces a distinct conformation in the transactivation domain of the LBD, providing structural evidence of the mechanism of antagonism.

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3,153 citations


Journal ArticleDOI
29 Nov 1996-Science
TL;DR: A nuclear magnetic resonance (NMR)-based method is described in which small organic molecules that bind to proximal subsites of a protein are identified, optimized, and linked together to produce high-affinity ligands and appears particularly useful in target-directed drug research.

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Abstract: A nuclear magnetic resonance (NMR)-based method is described in which small organic molecules that bind to proximal subsites of a protein are identified, optimized, and linked together to produce high-affinity ligands. The approach is called "SAR by NMR" because structure-activity relationships (SAR) are obtained from NMR. With this technique, compounds with nanomolar affinities for the FK506 binding protein were rapidly discovered by tethering two ligands with micromolar affinities. The method reduces the amount of chemical synthesis and time required for the discovery of high-affinity ligands and appears particularly useful in target-directed drug research.

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1,898 citations


Journal ArticleDOI
Gerhard Wolber, Thierry Langer1Institutions (1)
TL;DR: Three-dimensional pharmacophore models are constructed, which are sufficiently selective to identify the described binding mode and are thus a useful tool for in-silico screening of large compound databases.

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Abstract: From the historically grown archive of protein−ligand complexes in the Protein Data Bank small organic ligands are extracted and interpreted in terms of their chemical characteristics and features. Subsequently, pharmacophores representing ligand−receptor interaction are derived from each of these small molecules and its surrounding amino acids. Based on a defined set of only six types of chemical features and volume constraints, three-dimensional pharmacophore models are constructed, which are sufficiently selective to identify the described binding mode and are thus a useful tool for in-silico screening of large compound databases. The algorithms for ligand extraction and interpretation as well as the pharmacophore creation technique from the automatically interpreted data are presented and applied to a rhinovirus capsid complex as application example.

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1,264 citations


Journal ArticleDOI
TL;DR: Computer-aided drug discovery/design methods have played a major role in the development of therapeutically important small molecules for over three decades and theory behind the most important methods and recent successful applications are discussed.

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Abstract: Computer-aided drug discovery/design methods have played a major role in the development of therapeutically important small molecules for over three decades. These methods are broadly classified as either structure-based or ligand-based methods. Structure-based methods are in principle analogous to high-throughput screening in that both target and ligand structure information is imperative. Structure-based approaches include ligand docking, pharmacophore, and ligand design methods. The article discusses theory behind the most important methods and recent successful applications. Ligand-based methods use only ligand information for predicting activity depending on its similarity/dissimilarity to previously known active ligands. We review widely used ligand-based methods such as ligand-based pharmacophores, molecular descriptors, and quantitative structure-activity relationships. In addition, important tools such as target/ligand data bases, homology modeling, ligand fingerprint methods, etc., necessary for successful implementation of various computer-aided drug discovery/design methods in a drug discovery campaign are discussed. Finally, computational methods for toxicity prediction and optimization for favorable physiologic properties are discussed with successful examples from literature.

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997 citations


Journal ArticleDOI
Yi Liu1, Nathanael S. Gray2Institutions (2)
TL;DR: A structural analysis of binding modes of known human type II inhibitors are presented and it is demonstrated that they conform to a pharmacophore model that is currently being used to design a new generation of kinase inhibitors.

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Abstract: The majority of kinase inhibitors that have been developed so far—known as type I inhibitors—target the ATP binding site of the kinase in its active conformation, in which the activation loop is phosphorylated. Recently, crystal structures of inhibitors such as imatinib (STI571), BIRB796 and sorafenib (BAY43-9006)—known as type II inhibitors—have revealed a new binding mode that exploits an additional binding site immediately adjacent to the region occupied by ATP. This pocket is made accessible by an activation-loop rearrangement that is characteristic of kinases in an inactive conformation. Here, we present a structural analysis of binding modes of known human type II inhibitors and demonstrate that they conform to a pharmacophore model that is currently being used to design a new generation of kinase inhibitors.

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914 citations


Network Information
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Performance
Metrics
No. of papers in the topic in previous years
YearPapers
20224
2021509
2020436
2019407
2018380
2017453

Top Attributes

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Topic's top 5 most impactful authors

Keun Woo Lee

82 papers, 1.5K citations

Thierry Langer

76 papers, 3.9K citations

Daniela Schuster

49 papers, 1.3K citations

Gerhard Wolber

47 papers, 1.6K citations

Mutasem O. Taha

34 papers, 813 citations