Pharmacophore

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

Toward a pharmacophore for drugs inducing the long QT syndrome: insights from a CoMFA study of HERG K(+) channel blockers.

Abstract: In this paper, we present a pharmacophore for QT-prolonging drugs, along with a 3D QSAR (CoMFA) study for a series of very structurally variegate HERG K(+) channel blockers. The blockade of HERG K(+) channels is one of the most important molecular mechanisms through which QT-prolonging drugs increase cardiac action potential duration. Since QT prolongation is one of the most undesirable side effects of drugs, we first tried to identify the minimum set of molecular features responsible for this action and then we attempted to develop a quantitative model correlating the 3D stereoelectronic characteristics of the molecules with their HERG blocking potency. Having considered an initial set of 31 QT-prolonging drugs for which the HERG K(+) channel blocking activity was measured on mammalian transfected cells, we started the construction of a theoretical screening tool able to predict whether a new molecule can interact with the HERG channel and eventually induce the long QT syndrome. This in silico tool might be useful in the design of new drug candidates devoid of the physicochemical features likely to cause the above-mentioned side effect.

Pharmacophore modeling and three-dimensional database searching for drug design using catalyst.

Abstract: Perceiving a pharmacophore is the first essential step towards understanding the interaction between a receptor and a ligand. Once a pharmacophore is established, a beneficial use of it is 3D database searching to retrieve novel compounds that would match the pharmacophore, without necessarily duplicating the topological features of known active compounds (hence remain independent of existing patents). As the 3D searching technology has evolved over the years, it has been effectively used for lead optimization, combinatorial library focusing, as well as virtual high-throughput screening. Clearly established as one of the successful computational tools in rational drug design, we present in this review article a brief history of the evolution of this technology and detailed algorithms of Catalyst, the latest 3D searching software to be released. We also provide brief summary of published successes with this technology, including two recent patent applications.

New Arylthioindoles: Potent Inhibitors of Tubulin Polymerization. 2. Structure−Activity Relationships and Molecular Modeling Studies

Abstract: Arylthioindoles (ATIs) that possess a 3-methoxyphenylthio or a 3,5-dimethoxyphenylthio moiety at position 2 of the indole ring were effective tubulin assembly inhibitors, but weak inhibitors of MCF-7 cell growth. ATIs bearing a 3-(3,4,5-trimethoxyphenyl)thio moiety were potent tubulin polymerization inhibitors, with IC50s in the 2.0 (35) to 4.5 (37) ?M range. They also inhibited MCF-7 cell growth at nanomolar concentrations. The 3,4,5-trimethoxy substituted ATIs showed potencies comparable to those of the reference compounds colchicine and combretastatin A-4 in both tubulin assembly and cell growth inhibition assays. Dynamics simulation studies correlate well with the observed experimental data. Furthermore, from careful analysis of the biological and in silico data, we can now hypothesize a basic pharmacophore for this class of compounds.

Three-Dimensional Pharmacophore Methods in Drug Discovery

Abstract: Andrew R. Leach,* ) Valerie J. Gillet, Richard A. Lewis, and Robin Taylor Computational and Structural Chemistry, GlaxoSmithKline Research & Development, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K., Department of Information Studies, University of Sheffield, Regent Court, 211 Portobello Street, Sheffield S1 4DP, U.K., Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland, and Taylor Cheminformatics Software, 54 Sherfield Avenue, Rickmansworth, Herts WD3 1NL, U.K.

Tyrphostins. 2. Heterocyclic and alpha-substituted benzylidenemalononitrile tyrphostins as potent inhibitors of EGF receptor and ErbB2/neu tyrosine kinases.

Abstract: We have previously described a novel series of low molecular weight protein tyrosine kinase inhibitors which we named tyrphostins. The characteristic active pharmacophore of these compounds was the hydroxy-cis-benzylidenemalononitrile moiety. In this article we describe three novel groups of tyrphostins: (i) one group has the phenolic moiety of the cis-benzylidenemalononitrile replaced either with other substituted benzenes or with heteroaromatic rings, (ii) another is a series of conformationally constrained derivatives of hydroxy-cis-benzylidenemalononitriles in which the malononitrile moiety is fixed relative to the aromatic ring, and (iii) two groups of compounds in which the position trans to the benzenemalononitrile has been substituted by ketones and amides. Among the novel tyrphostins examined we found inhibitors which discriminate between the highly homologous EGF receptor kinase (HER1) and ErbB2/neu kinase (HER2). These findings may lead to selective tyrosine kinase blockers for the treatment of diseases in which ErbB2/neu is involved.