Publications by authors named "Christine M Richardson"

12 Publications

  • Page 1 of 1

Classifying shape coverage in fragment libraries using a fingerprinting approach.

Bioorg Med Chem Lett 2015 3;25(10):2089-95. Epub 2015 Apr 3.

Charles River Laboratories, Chesterford Research Park, Saffron Walden, Essex CB10 1XL, UK.

Fragment screening is one approach to hit identification for early stage drug discovery projects. Like any screening library, diversity is needed in fragment libraries. This includes coverage of shape and electrostatic space, as well as chemotype diversity. A new, easily interpretable shape-based fingerprint is described and its utility in probing fragment library content is demonstrated using a Rule of Three library from Maybridge. This method explicitly considers size as a component of shape. It allows interrogation of shape space on both a per conformer and a per molecule level, and includes a measure of flexibility. This allows for the identification of highly flexible compounds and their exclusion from the analysis. A comparison with two literature methods, the triangle plot approach of Sauer and Schwarz and the plane of best fit method of Firth et al., is also included.
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http://dx.doi.org/10.1016/j.bmcl.2015.03.082DOI Listing
January 2016

Design, synthesis, and biological evaluation of potent and selective class IIa histone deacetylase (HDAC) inhibitors as a potential therapy for Huntington's disease.

J Med Chem 2013 Dec 5;56(24):9934-54. Epub 2013 Dec 5.

BioFocus , Chesterford Research Park, Saffron Walden, Essex, CB10 1XL, United Kingdom.

Inhibition of class IIa histone deacetylase (HDAC) enzymes have been suggested as a therapeutic strategy for a number of diseases, including Huntington's disease. Catalytic-site small molecule inhibitors of the class IIa HDAC4, -5, -7, and -9 were developed. These trisubstituted diarylcyclopropanehydroxamic acids were designed to exploit a lower pocket that is characteristic for the class IIa HDACs, not present in other HDAC classes. Selected inhibitors were cocrystallized with the catalytic domain of human HDAC4. We describe the first HDAC4 catalytic domain crystal structure in a "closed-loop" form, which in our view represents the biologically relevant conformation. We have demonstrated that these molecules can differentiate class IIa HDACs from class I and class IIb subtypes. They exhibited pharmacokinetic properties that should enable the assessment of their therapeutic benefit in both peripheral and CNS disorders. These selective inhibitors provide a means for evaluating potential efficacy in preclinical models in vivo.
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http://dx.doi.org/10.1021/jm4011884DOI Listing
December 2013

Identification of novel adenosine A(2A) receptor antagonists by virtual screening.

J Med Chem 2012 Mar 23;55(5):1904-9. Epub 2012 Feb 23.

Heptares Therapeutics Limited, BioPark, Broadwater Road, Welwyn Garden City, Hertfordshire AL7 3AX, UK.

Virtual screening was performed against experimentally enabled homology models of the adenosine A(2A) receptor, identifying a diverse range of ligand efficient antagonists (hit rate 9%). By use of ligand docking and Biophysical Mapping (BPM), hits 1 and 5 were optimized to potent and selective lead molecules (11-13 from 5, pK(I) = 7.5-8.5, 13- to >100-fold selective versus adenosine A(1); 14-16 from 1, pK(I) = 7.9-9.0, 19- to 59-fold selective).
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http://dx.doi.org/10.1021/jm201455yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3308209PMC
March 2012

A comparative study of fragment screening methods on the p38α kinase: new methods, new insights.

J Comput Aided Mol Des 2011 Jul 6;25(7):677-87. Epub 2011 Jul 6.

BioFocus, Chesterford Research Park, Saffron Walden, Essex, CB10 1XL, United Kingdom.

The stress-activated kinase p38α was used to evaluate a fragment-based drug discovery approach using the BioFocus fragment library. Compounds were screened by surface plasmon resonance (SPR) on a Biacore(™) T100 against p38α and two selectivity targets. A sub-set of our library was the focus of detailed follow-up analyses that included hit confirmation, affinity determination on 24 confirmed, selective hits and competition assays of these hits with respect to a known ATP binding site inhibitor. In addition, functional activity against p38α was assessed in a biochemical assay using a mobility shift platform (LC3000, Caliper LifeSciences). A selection of fragments was also evaluated using fluorescence lifetime (FLEXYTE(™)) and microscale thermophoresis (Nanotemper) technologies. A good correlation between the data for the different assays was found. Crystal structures were solved for four of the small molecules complexed to p38α. Interestingly, as determined both by X-ray analysis and SPR competition experiments, three of the complexes involved the fragment at the ATP binding site, while the fourth compound bound in a distal site that may offer potential as a novel drug target site. A first round of optimization around the remotely bound fragment has led to the identification of a series of triazole-containing compounds. This approach could form the basis for developing novel and active p38α inhibitors. More broadly, it illustrates the power of combining a range of biophysical and biochemical techniques to the discovery of fragments that facilitate the development of novel modulators of kinase and other drug targets.
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http://dx.doi.org/10.1007/s10822-011-9454-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3155752PMC
July 2011

Discovery of cell-active phenyl-imidazole Pin1 inhibitors by structure-guided fragment evolution.

Bioorg Med Chem Lett 2010 Nov 17;20(22):6483-8. Epub 2010 Sep 17.

Vernalis (R&D) Ltd, Granta Park, Great Abington, Cambridge CB21 6GB, United Kingdom.

Pin1 is an emerging oncology target strongly implicated in Ras and ErbB2-mediated tumourigenesis. Pin1 isomerizes bonds linking phospho-serine/threonine moieties to proline enabling it to play a key role in proline-directed kinase signalling. Here we report a novel series of Pin1 inhibitors based on a phenyl imidazole acid core that contains sub-μM inhibitors. Compounds have been identified that block prostate cancer cell growth under conditions where Pin1 is essential.
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http://dx.doi.org/10.1016/j.bmcl.2010.09.063DOI Listing
November 2010

Structure-guided design of alpha-amino acid-derived Pin1 inhibitors.

Bioorg Med Chem Lett 2010 Jan 22;20(2):586-90. Epub 2009 Nov 22.

Vernalis (R&D) Ltd, Granta Park, Great Abington, Cambridge CB21 6GB, United Kingdom.

The peptidyl prolyl cis/trans isomerase Pin1 is a promising molecular target for anti-cancer therapeutics. Here we report the structure-guided evolution of an indole 2-carboxylic acid fragment hit into a series of alpha-benzimidazolyl-substituted amino acids. Examples inhibited Pin1 activity with IC(50) <100nM, but were inactive on cells. Replacement of the benzimidazole ring with a naphthyl group resulted in a 10-50-fold loss in ligand potency, but these examples downregulated biomarkers of Pin1 activity and blocked proliferation of PC3 cells.
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http://dx.doi.org/10.1016/j.bmcl.2009.11.090DOI Listing
January 2010

Discovery of a potent CDK2 inhibitor with a novel binding mode, using virtual screening and initial, structure-guided lead scoping.

Bioorg Med Chem Lett 2007 Jul 6;17(14):3880-5. Epub 2007 May 6.

Vernalis (R&D) Ltd, Granta Park, Cambridge CB21 6GB, UK.

Virtual screening against a pCDK2/cyclin A crystal structure led to the identification of a potent and novel CDK2 inhibitor, which exhibited an unusual mode of interaction with the kinase binding motif. With the aid of X-ray crystallography and modelling, a medicinal chemistry strategy was implemented to probe the interactions seen in the crystal structure and to establish SAR. A fragment-based approach was also considered but a different, more conventional, binding mode was observed. Compound selectivity against GSK-3beta was improved using a rational design strategy, with crystallographic verification of the CDK2 binding mode.
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http://dx.doi.org/10.1016/j.bmcl.2007.04.110DOI Listing
July 2007

Identification of non-furan containing A2A antagonists using database mining and molecular similarity approaches.

Bioorg Med Chem Lett 2006 Dec 12;16(23):5993-7. Epub 2006 Sep 12.

Vernalis (R&D) Ltd, Granta Park, Cambridge, CB1 6GB, UK.

Database searching led to the identification of potent A(2A) antagonists which do not contain the privileged furan moiety and which show selectivity over A(1) receptors. Simple substructure searching on a proprietary database identified compounds with activities in the low nM range. A targeted approach to the identification of non-furan containing compounds resulted in the identification of two novel series, with potency, selectivity and directional SAR from screening 113 compounds.
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http://dx.doi.org/10.1016/j.bmcl.2006.08.116DOI Listing
December 2006

Triazolo[1,5-a]pyrimidines as novel CDK2 inhibitors: protein structure-guided design and SAR.

Bioorg Med Chem Lett 2006 Mar 1;16(5):1353-7. Epub 2005 Dec 1.

Vernalis (R&D) Ltd, Granta Park, Great Abington, Cambridge CB1 6GB, UK.

Crystallographic and modelling data, in conjunction with a medicinal chemistry template-hopping approach, led to the identification of a series of novel and potent inhibitors of human cyclin-dependent kinase 2 (CDK2), with selectivity over glycogen synthase kinase-3beta (GSK-3beta). One example had a CDK2 IC(50) of 120 nM and showed selectivity over GSK-3beta of 167-fold.
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http://dx.doi.org/10.1016/j.bmcl.2005.11.048DOI Listing
March 2006

Structure-guided design of pyrazolo[1,5-a]pyrimidines as inhibitors of human cyclin-dependent kinase 2.

Bioorg Med Chem Lett 2005 Feb;15(4):863-7

Vernalis (R&D) Ltd, Granta Park, Great Abington, Cambridge CB1 6GB, United Kingdom.

The protein structure guided design of a series of pyrazolo[1,5-a]pyrimidines with high potency for human cyclin-dependent kinase 2 (CDK2) is described. Some examples were shown to inhibit the growth of human colon tumour cells, were equipotent for CDK1 and were selective against GSK-3beta and other kinases.
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http://dx.doi.org/10.1016/j.bmcl.2004.12.073DOI Listing
February 2005

Staphylococcus aureus gyrase-quinolone-DNA ternary complexes fail to arrest replication fork progression in vitro. Effects of salt on the DNA binding mode and the catalytic activity of S. aureus gyrase.

J Biol Chem 2003 Mar 23;278(10):8861-8. Epub 2002 Dec 23.

Department of Pharmacology, University of Minnesota Medical School, Minneapolis 55455, USA.

Type II topoisomerases bind to DNA at the catalytic domain across the DNA gate. DNA gyrases also bind to DNA at the non-homologous C-terminal domain of the GyrA subunit, which causes the wrapping of DNA about itself. This unique mode of DNA binding allows gyrases to introduce the negative supercoils into DNA molecules. We have investigated the biochemical characteristics of Staphylococcus aureus (S. aureus) gyrase. S. aureus gyrase is known to require high concentrations of potassium glutamate (K-Glu) for its supercoiling activity. However, high concentrations of K-Glu are not required for its relaxation and decatenation activities. This is due to the requirement of high concentrations of K-Glu for S. aureus gyrase-mediated wrapping of DNA. These results suggest that S. aureus gyrase can bind to DNA at the catalytic domain independent of K-Glu concentration, but high concentrations of K-Glu are required for the binding of the C-terminal domain of GyrA to DNA and the wrapping of DNA. Thus, salt modulates the DNA binding mode and the catalytic activity of S. aureus gyrase. Quinolone drugs can stimulate the formation of covalent S. aureus gyrase-DNA complexes, but high concentrations of K-Glu inhibit the formation of S. aureus gyrase-quinolone-DNA ternary complexes. In the absence of K-Glu, ternary complexes formed with S. aureus gyrase cannot arrest replication fork progression in vitro, demonstrating that the formation of a wrapped ternary complex is required for replication fork arrest by a S. aureus gyrase-quinolone-DNA ternary complex.
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http://dx.doi.org/10.1074/jbc.M209207200DOI Listing
March 2003

The antimicrobial natural product chuangxinmycin and some synthetic analogues are potent and selective inhibitors of bacterial tryptophanyl tRNA synthetase.

Bioorg Med Chem Lett 2002 Nov;12(21):3171-4

GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK.

The antimicrobial natural product chuangxinmycin has been found to be a potent and selective inhibitor of bacterial tryptophanyl tRNA synthetase (WRS). A number of analogues have been synthesised. The interaction with WRS appears to be highly constrained, as only sterically smaller analogues afforded significant inhibition. The only analogue to show inhibition comparable to chuangxinmycin also had antibacterial activity. WRS inhibition may contribute to the antibacterial action of chuangxinmycin.
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http://dx.doi.org/10.1016/s0960-894x(02)00604-2DOI Listing
November 2002