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Dive into the research topics where Nathan Brown is active.

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Featured researches published by Nathan Brown.


Journal of Medicinal Chemistry | 2012

Druggability analysis and structural classification of bromodomain acetyl-lysine binding sites.

Lewis R. Vidler; Nathan Brown; Stefan Knapp; Swen Hoelder

Bromodomains are readers of the epigenetic code that specifically bind acetyl-lysine containing recognition sites on proteins. Recently the BET family of bromodomains has been demonstrated to be druggable through the discovery of potent inhibitors, sparking an interest in protein–protein interaction inhibitors that directly target gene transcription. Here, we assess the druggability of diverse members of the bromodomain family using SiteMap and show that there are significant differences in predicted druggability. Furthermore, we trace these differences in druggability back to unique amino acid signatures in the bromodomain acetyl-lysine binding sites. These signatures were then used to generate a new classification of the bromodomain family, visualized as a classification tree. This represents the first analysis of this type for the bromodomain family and can prove useful in the discovery of inhibitors, particularly for anticipating screening hit rates, identifying inhibitors that can be explored for lead hopping approaches, and selecting proteins for selectivity screening.


Mini-reviews in Medicinal Chemistry | 2006

On scaffolds and hopping in medicinal chemistry.

Nathan Brown; Edgar Jacoby

The molecular scaffold is an oft-cited concept in medicinal chemistry suggesting that the definition of what makes a scaffold is rigorous and objective. However, this is far from the case with the definition of a scaffold being highly dependent on the particular viewpoint of a given scientist. It follows, therefore, that the definition of scaffold hopping and, more importantly, the detection of what constitutes a scaffold hop, is also ill-defined and highly subjective. Essentially, it is agreed that scaffolds should be substantially different from each other, although significantly similar to each other, to constitute a hop. In the latter, the scaffolds must permit a similar geometric arrangement of functional groups to permit the mode of action. However, this leaves the paradox of how to describe both scaffold similarity and dissimilarity simultaneously. In this paper, the current statuses of scaffolds and scaffold hopping are reviewed based on published examples of scaffold hopping from the literature. An investigation of the degree to which it is possible to formulate a more rigorous definition of scaffolds and hopping in the context of molecular topologies is considered. These techniques are adapted from chemoinformatics to be applied in the design of new medicinal compounds.


Molecular Informatics | 2010

Bioisosteric Replacement and Scaffold Hopping in Lead Generation and Optimization.

Sarah R. Langdon; Peter Ertl; Nathan Brown

Bioisosteric replacement and scaffold hopping are twin methods used in drug design to improve the synthetic accessibility, potency and drug like properties of a compound and to move into novel chemical space. Bioisosteric replacement involves swapping functional groups of a molecule with other functional groups that have similar biological properties. Scaffold hopping is the replacement of the core framework of a molecule with another scaffold that will improve the properties of the molecule or to find similar potent compounds that exist in novel chemical space. This review outlines the key concepts, importance and challenges of both methods using examples and comparisons of techniques available for finding bioisosteric replacements and scaffold hops. There are many methods available for bioisosteric replacement and scaffold hopping, all with their own advantages and disadvantages. Drug design projects would benefit from a combination of these methods to retrieve diverse and complimentary results. Continuing progress in these fields will allow further validation of both methods as well as the accumulation of knowledge on bioisosteres and possible scaffold replacements.


Journal of Medicinal Chemistry | 2013

Discovery of Novel Small-Molecule Inhibitors of BRD4 Using Structure-Based Virtual Screening.

Lewis R. Vidler; Panagis Filippakopoulos; Oleg Fedorov; Sarah Picaud; Sarah Martin; Michael Tomsett; Hannah Woodward; Nathan Brown; Stefan Knapp; Swen Hoelder

Bromodomains (BRDs) are epigenetic readers that recognize acetylated-lysine (KAc) on proteins and are implicated in a number of diseases. We describe a virtual screening approach to identify BRD inhibitors. Key elements of this approach are the extensive design and use of substructure queries to compile a set of commercially available compounds featuring novel putative KAc mimetics and docking this set for final compound selection. We describe the validation of this approach by applying it to the first BRD of BRD4. The selection and testing of 143 compounds lead to the discovery of six novel hits, including four unprecedented KAc mimetics. We solved the crystal structure of four hits, determined their binding mode, and improved their potency through synthesis and the purchase of derivatives. This work provides a validated virtual screening approach that is applicable to other BRDs and describes novel KAc mimetics that can be further explored to design more potent inhibitors.


Journal of Chemical Information and Modeling | 2011

Scaffold Diversity of Exemplified Medicinal Chemistry Space

Sarah R. Langdon; Nathan Brown; Julian Blagg

The scaffold diversity of 7 representative commercial and proprietary compound libraries is explored for the first time using both Murcko frameworks and Scaffold Trees. We show that Level 1 of the Scaffold Tree is useful for the characterization of scaffold diversity in compound libraries and offers advantages over the use of Murcko frameworks. This analysis also demonstrates that the majority of compounds in the libraries we analyzed contain only a small number of well represented scaffolds and that a high percentage of singleton scaffolds represent the remaining compounds. We use Tree Maps to clearly visualize the scaffold space of representative compound libraries, for example, to display highly populated scaffolds and clusters of structurally similar scaffolds. This study further highlights the need for diversification of compound libraries used in hit discovery by focusing library enrichment on the synthesis of compounds with novel or underrepresented scaffolds.


The EMBO Journal | 1995

The crystal structure of p13suc1, a p34cdc2-interacting cell cycle control protein.

Jane A. Endicott; Martin Noble; Elspeth F. Garman; Nathan Brown; Rasmussen B; Paul Nurse; Louise N. Johnson

p13suc1 binds to p34cdc2 kinase and is essential for cell cycle progression in eukaryotic cells. The crystal structure of S.pombe p13suc1 has been solved to 2.7 A resolution using data collected at the ESRF source, Grenoble, from both native crystals and crystals of a seleno‐methionine derivative. The starting point for structure solution was the determination of the six selenium sites by direct methods. The structure is dominated by a four‐stranded beta‐sheet, with four further alpha‐helical regions. p13suc1 crystallizes as a dimer in the asymmetric unit stabilized by the binding of two zinc ions. A third zinc site stabilizes the higher‐order crystal packing. The sites are consistent with a requirement for zinc during crystal growth. A likely site for p13suc1‐protein interaction is immediately evident on one face of the p13suc1 surface. This region comprises a group of conserved, exposed aromatic and hydrophobic residues below a flexible negatively charged loop. A conserved positively charged area would also present a notable surface feature in the monomer, but is buried at the dimer interface. p13suc1 is larger than its recently solved human homologue p9CKS2, with the extra polypeptide forming a helical N‐terminal extension and a surface loop between alpha‐helices 3 and 4. Notably, p13suc1 does not show the unusual beta‐strand exchange that creates an intimate p9CKS2 dimer. p13suc1 cannot oligomerize to form a stable hexamer as has been proposed for p9CKS2.


Drug Discovery Today | 2013

Fragment-based hit identification: thinking in 3D

Andrew D. Morley; Angelo Pugliese; Kristian Birchall; Justin Bower; Paul E. Brennan; Nathan Brown; Tim Chapman; Martin Drysdale; Ian H. Gilbert; Swen Hoelder; Allan M. Jordan; Steven V. Ley; Andy Merritt; David Miller; Martin E. Swarbrick; Paul G. Wyatt

The identification of high-quality hits during the early phases of drug discovery is essential if projects are to have a realistic chance of progressing into clinical development and delivering marketed drugs. As the pharmaceutical industry goes through unprecedented change, there are increasing opportunities to collaborate via pre-competitive networks to marshal multifunctional resources and knowledge to drive impactful, innovative science. The 3D Fragment Consortium is developing fragment-screening libraries with enhanced 3D characteristics and evaluating their effect on the quality of fragment-based hit identification (FBHI) projects.


ACM Computing Surveys | 2009

Chemoinformatics—an introduction for computer scientists

Nathan Brown

Chemoinformatics is an interface science aimed primarily at discovering novel chemical entities that will ultimately result in the development of novel treatments for unmet medical needs, although these same methods are also applied in other fields that ultimately design new molecules. The field combines expertise from, among others, chemistry, biology, physics, biochemistry, statistics, mathematics, and computer science. In this general review of chemoinformatics the emphasis is placed on describing the general methods that are routinely applied in molecular discovery and in a context that provides for an easily accessible article for computer scientists as well as scientists from other numerate disciplines.


Drug Discovery Today: Technologies | 2013

Multi-objective optimization methods in drug design

Christos A. Nicolaou; Nathan Brown

Drug discovery is a challenging multi-objective problem where numerous pharmaceutically important objectives need to be adequately satisfied for a solution to be found. The problem is characterized by vast, complex solution spaces further perplexed by the presence of conflicting objectives. Multi-objective optimization methods, designed specifically to address such problems, have been introduced to the drug discovery field over a decade ago and have steadily gained in acceptance ever since. This paper reviews the latest multi-objective methods and applications reported in the literature, specifically in quantitative structure–activity modeling, docking, de novo design and library design. Further, the paper reports on related developments in drug discovery research and advances in the multi-objective optimization field.


Journal of Biological Chemistry | 2010

Structural Basis of Poly(Adp-Ribose) Recognition by the Multizinc Binding Domain of Checkpoint with Forkhead-Associated and Ring Domains (Chfr).

Jasmeen Oberoi; Mark W. Richards; Simon Crumpler; Nathan Brown; Julian Blagg; Richard Bayliss

Cellular stress in early mitosis activates the antephase checkpoint, resulting in the decondensation of chromosomes and delayed mitotic progression. Checkpoint with forkhead-associated and RING domains (CHFR) is central to this checkpoint, and its activity is ablated in many tumors and cancer cell lines through promoter hypermethylation or mutation. The interaction between the PAR-binding zinc finger (PBZ) of CHFR and poly(ADP-ribose) (PAR) is crucial for a functional antephase checkpoint. We determined the crystal structure of the cysteine-rich region of human CHFR (amino acids 425–664) to 1.9 Å resolution, which revealed a multizinc binding domain of elaborate topology within which the PBZ is embedded. The PBZ of CHFR closely resembles the analogous motifs from aprataxin-like factor and CG1218-PA, which lie within unstructured regions of their respective proteins. Based on co-crystal structures of CHFR bound to several different PAR-like ligands (adenosine 5′-diphosphoribose, adenosine monophosphate, and P1P2-diadenosine 5′-pyrophosphate), we made a model of the CHFR-PAR interaction, which we validated using site-specific mutagenesis and surface plasmon resonance. The PBZ motif of CHFR recognizes two adenine-containing subunits of PAR and the phosphate backbone that connects them. More generally, PBZ motifs may recognize different numbers of PAR subunits as required to carry out their functions.

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Julian Blagg

Institute of Cancer Research

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Butrus Atrash

Institute of Cancer Research

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Simon Crumpler

Institute of Cancer Research

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Amir Faisal

Institute of Cancer Research

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Magda N. Kosmopoulou

Institute of Cancer Research

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Vassilios Bavetsias

Institute of Cancer Research

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Chongbo Sun

Institute of Cancer Research

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Florence I. Raynaud

Institute of Cancer Research

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