Author: Vischer, Henry F. ; de Graaf, Chris ; Nijmeijer, Saskia ; Leurs, Rob ; Kooistra, Albert J. ; de Esch, Iwan J. P. ; Sirci, Francesco ; Kuijer, Martien ; Mannhold, Raimund ; Istyastono, Enade P. ; Wijtmans, Maikel

Virtual fragment screening (VFS) is a promising new method that uses computer models to identify small, fragment-like biologically active molecules as useful starting points for fragment-based drug discovery (FBDD). Training sets of true active and inactive fragment-like molecules to construct and validate target customized VFS methods are however lacking. We have for the first time explored the possibilities and challenges of VFS using molecular fingerprints derived from a unique set of fragment affinity data for the histamine H(3) receptor (H(3)R), a pharmaceutically relevant G protein-coupled receptor (GPCR). Optimized FLAP (Fingerprints of Ligands and Proteins) models containing essential molecular interaction fields that discriminate known H(3)R binders from inactive molecules were successfully used for the identification of new H(3)R ligands. Prospective virtual screening of 156,090 molecules yielded a high hit rate of 62% (18 of the 29 tested) experimentally confirmed novel fragment-like H(3)R ligands that offer new potential starting points for the design of H(3)R targeting drugs. The first construction and application of customized FLAP models for the discovery of fragment-like biologically active molecules demonstrates that VFS is an efficient way to explore protein-fragment interaction space in silico.

11 Nov 2010·Journal of Medicinal ChemistryQ1 · MEDICINE

Diaryldiamines with Dual Inhibition of the Histamine H₃ Receptor and the Norepinephrine Transporter and the Efficacy of 4-(3-(Methylamino)-1-phenylpropyl)-6-(2-(pyrrolidin-1-yl)ethoxy)naphthalen-1-ol in Pain

Q1 · MEDICINE

Article

Author: Wensink, Erica J. ; Strakhova, Marina I. ; Altenbach, Robert J. ; Garrison, Tiffany Runyan ; Brioni, Jorge D. ; Wetter, Jill M. ; Cowart, Marlon D. ; Hsieh, Gin C. ; Manelli, Arlene M. ; Honore, Prisca ; Carr, Tracy L. ; Black, Lawrence A. ; Marsh, Kennan C.

A series of compounds was designed as dual inhibitors of the H(3) receptor and the norepinephrine transporter. Compound 5 (rNET K(i) = 14 nM; rH(3)R K(i) = 37 nM) was found to be efficacious in a rat model of osteoarthritic pain.

100 Deals associated with H3 receptor antagonists and NET inhibitors(Abbott Laboratories)

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Indication	Highest Phase	Country/Location	Organization	Date
Inflammatory pain	Preclinical	United States	Abbott Laboratories	11 Nov 2010

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H3 receptor antagonists and NET inhibitors(Abbott Laboratories)

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