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      Design, Synthesis, and Structure–Activity Relationships of Highly Potent 5-HT 3 Receptor Ligands

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          Abstract

          The 5-HT 3 receptor, a pentameric ligand-gated ion channel (pLGIC), is an important therapeutic target. During a recent fragment screen, 6-chloro- N-methyl-2-(4-methyl-1,4-diazepan-1-yl)quinazolin-4-amine ( 1) was identified as a 5-HT 3R hit fragment. Here we describe the synthesis and structure–activity relationships (SAR) of a series of (iso)quinoline and quinazoline compounds that were synthesized and screened for 5-HT 3R affinity using a [ 3H]granisetron displacement assay. These studies resulted in the discovery of several high affinity ligands of which compound 22 showed the highest affinity (p K i > 10) for the 5-HT 3 receptor. The observed SAR is in agreement with established pharmacophore models for 5-HT 3 ligands and is used for ligand–receptor binding mode prediction using homology modeling and in silico docking approaches.

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          Improved protein-ligand docking using GOLD.

          Marcel Verdonk, Jason Cole, Michael J Hartshorn … (2003)
          The Chemscore function was implemented as a scoring function for the protein-ligand docking program GOLD, and its performance compared to the original Goldscore function and two consensus docking protocols, "Goldscore-CS" and "Chemscore-GS," in terms of docking accuracy, prediction of binding affinities, and speed. In the "Goldscore-CS" protocol, dockings produced with the Goldscore function are scored and ranked with the Chemscore function; in the "Chemscore-GS" protocol, dockings produced with the Chemscore function are scored and ranked with the Goldscore function. Comparisons were made for a "clean" set of 224 protein-ligand complexes, and for two subsets of this set, one for which the ligands are "drug-like," the other for which they are "fragment-like." For "drug-like" and "fragment-like" ligands, the docking accuracies obtained with Chemscore and Goldscore functions are similar. For larger ligands, Goldscore gives superior results. Docking with the Chemscore function is up to three times faster than docking with the Goldscore function. Both combined docking protocols give significant improvements in docking accuracy over the use of the Goldscore or Chemscore function alone. "Goldscore-CS" gives success rates of up to 81% (top-ranked GOLD solution within 2.0 A of the experimental binding mode) for the "clean list," but at the cost of long search times. For most virtual screening applications, "Chemscore-GS" seems optimal; search settings that give docking speeds of around 0.25-1.3 min/compound have success rates of about 78% for "drug-like" compounds and 85% for "fragment-like" compounds. In terms of producing binding energy estimates, the Goldscore function appears to perform better than the Chemscore function and the two consensus protocols, particularly for faster search settings. Even at docking speeds of around 1-2 min/compound, the Goldscore function predicts binding energies with a standard deviation of approximately 10.5 kJ/mol. Copyright 2003 Wiley-Liss, Inc.
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            Acetylcholine receptor channel imaged in the open state.

            N Unwin (1995)
            The structure of the open-channel form of the acetylcholine receptor has been determined from electron images of Torpedo ray postsynaptic membranes activated by brief (< 5 ms) mixing with droplets containing acetylcholine. Comparison with the closed-channel form shows that acetylcholine initiates small rotations of the subunits in the extracellular domain, which trigger a change in configuration of alpha-helices lining the membrane-spanning pore. The open pore tapers towards the intracellular membrane face, where it is shaped by a 'barrel' of alpha-helices having a pronounced right-handed twist.
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              Modeling water molecules in protein-ligand docking using GOLD.

              J. Nissink, Dáithí Murray, Michael J Hartshorn … (2005)
              We implemented a novel approach to score water mediation and displacement in the protein-ligand docking program GOLD. The method allows water molecules to switch on and off and to rotate around their three principal axes. A constant penalty, sigma(p), representing the loss of rigid-body entropy, is added for water molecules that are switched on, hence rewarding water displacement. We tested the methodology in an extensive validation study. First, sigma(p) is optimized against a training set of 58 protein-ligand complexes. For this training set, our algorithm correctly predicts water mediation/displacement in approximately 92% of the cases. We observed small improvements in the quality of the predicted binding modes for water-mediated complexes. In the second part of this work, an entirely independent set of 225 complexes is used. For this test set, our algorithm correctly predicts water mediation/displacement in approximately 93% of the cases. Improvements in binding mode quality were observed for individual water-mediated complexes.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Med Chem
                Journal ID (iso-abbrev): J. Med. Chem
                Journal ID (publisher-id): jm
                Journal ID (coden): jmcmar
                Title: Journal of Medicinal Chemistry
                Publisher: American Chemical Society
                ISSN (Print): 0022-2623
                ISSN (Electronic): 1520-4804
                Publication date (Electronic): 24 September 2012
                Publication date (Print): 25 October 2012
                Volume: 55
                Issue: 20
                Pages: 8603-8614
                Affiliations
                [† ]Leiden/Amsterdam Center of Drug Research (LACDR), Amsterdam Institute for Molecules Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Sciences, VU University Amsterdam , Amsterdam, The Netherlands.
                [§ ]Department of Biochemistry, University of Cambridge , Cambridge, United Kingdom
                Author notes
                [* ]Phone: +31205987841. Fax: +31205987610. E-mail: i.de.esch@ 123456vu.nl . Division of Medicinal Chemistry, Faculty of Sciences, VU University Amsterdam, Room: G-379a, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
                Article
                DOI: 10.1021/jm300801u
                PMC ID: 3504484
                PubMed ID: 23006041
                SO-VID: 79aa1cea-7386-481e-80b3-b4587a161a86
                Copyright © Copyright © 2012 American Chemical Society
                License:

                This is an open-access article distributed under the ACS AuthorChoice Terms & Conditions. Any use of this article, must conform to the terms of that license which are available at http://pubs.acs.org.

                History
                Date received : 21 May 2012
                Categories
                Subject: Article
                Custom metadata
                document-id-old-9 jm300801u
                document-id-new-14 jm-2012-00801u
                ccc-price

                ScienceOpen disciplines: Pharmaceutical chemistry
                Data availability:
                ScienceOpen disciplines: Pharmaceutical chemistry

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