DSpace Community: Cambridge Chemistry

Total Synthesis of (−) - Rhizopodin

Sun, 05 May 2013 23:00:00 GMT

Title: Total Synthesis of (−) - Rhizopodin Authors: Dalby, Stephen M.; Goodwin - Tindall, Jake; Paterson, Ian Abstract: Core assembly: The total synthesis of the myxobacterial metabolite rhizopodin, a potent actin-binding anticancer agent, has been achieved. The modular synthesis utilizes a common C1–C22 monomeric unit to assemble the dimeric 38-membered macrodiolide core, which was elaborated by a bidirectional boron-mediated aldol reaction to install the characteristic side-chains. The final global deprotection was critically dependent on the correct choice of silyl protecting groups at C16/C16′. Description: This is the peer reviewed version of the following article: Dalby, S.M, Goodwin-Tindall, J., Paterson, I. (2013), Total Synthesis of (−)-Rhizopodin. Angew. Chem. Int. Ed., which has been published in final form at http://dx.doi.org/‎10.1002/anie.201301978. This article may be used for non-commercial purposes in accordance With Wiley Terms and Conditions for self-archiving http://olabout.wiley.com/WileyCDA/Section/id-815640.html

Computational approaches to predicting drug induced toxicity

Tue, 08 Jan 2013 00:00:00 GMT

Title: Computational approaches to predicting drug induced toxicity Authors: Marchese Robinson, Richard Liam Abstract: Novel approaches and models for predicting drug induced toxicity in silico are presented. Typically, these were based on Quantitative Structure-Activity Relationships (QSAR). The following endpoints were modelled: mutagenicity, carcinogenicity, inhibition of the hERG ion channel and the associated arrhythmia - Torsades de Pointes. A consensus model was developed based on Derek for WindowsTM and Toxtree and used to filter compounds as part of a collaborative effort resulting in the identification of potential starting points for anti-tuberculosis drugs. Based on the careful selection of data from the literature, binary classifiers were generated for the identification of potent hERG inhibitors. These were found to perform competitively with, or better than, those computational approaches previously presented in the literature. Some of these models were generated using Winnow, in conjunction with a novel proposal for encoding molecular structures as required by this algorithm. The Winnow models were found to perform comparably to models generated using the Support Vector Machine and Random Forest algorithms. These studies also emphasised the variability in results which may be obtained when applying the same approaches to different train/test combinations. Novel approaches to combining chemical information with Ultrafast Shape Recognition (USR) descriptors are introduced: Atom Type USR (ATUSR) and a combination between a proposed Atom Type Fingerprint (ATFP) and USR (USR-ATFP). These were applied to the task of predicting protein-ligand interactions - including the prediction of hERG inhibition. Whilst, for some of the datasets considered, either ATUSR or USR-ATFP was found to perform marginally better than all other descriptor sets to which they were compared, most differences were statistically insignificant. Further work is warranted to determine the advantages which ATUSR and USR-ATFP might offer with respect to established descriptor sets. The first attempts to construct QSAR models for Torsades de Pointes using predicted cardiac ion channel inhibitory potencies as descriptors are presented, along with the first evaluation of experimentally determined inhibitory potencies as an alternative, or complement to, standard descriptors. No (clear) evidence was found that 'predicted' ('experimental') 'IC-descriptors' improve performance. However, their value may lie in the greater interpretability they could confer upon the models. Building upon the work presented in the preceding chapters, this thesis ends with specific proposals for future research directions.

A Quasi-continuous Interpolation Scheme for Pathways between Distant Configurations

Mon, 27 Aug 2012 23:00:00 GMT

Title: A Quasi-continuous Interpolation Scheme for Pathways between Distant Configurations Authors: Carr, Joanne M; Wales, David J Abstract: A quasi-continuous interpolation scheme is introduced for characterising physically realistic initial pathways from which to initiate transition state searches and construct kinetic transition networks. Applications are presented for peptides, proteins, and a morphological transformation in an atomic cluster. A simple interpolating potential is first defined, which preserves the covalent bonding framework for the biomolecules. This potential is used to identify an interpolating path by minimising contributions from a connected set of images along with terms corresponding to minima in the interatomic distances between them. This procedure, combined with repulsive terms between unconstrained atoms, helps to circumvent unphysical geometries in the line segments between images. The most difficult cases, where linear interpolation would involve chain crossings, are treated by growing the structure an atom at a time using the interpolating potential. A second optimisation phase then introduces a fraction of the true potential. Permutational alignment is achieved using a shortest augmenting path algorithm based on the local environment. Description: This document is the unedited Author’s version of a Submitted Work that was subsequently accepted for publication in the Journal of Chemical Theory and Computation, copyright © American Chemical Society after peer review. To access the final edited and published work see http://dx.doi.org/10.1021/ct3004832

Open Content Mining

Sun, 23 Sep 2012 23:00:00 GMT

Title: Open Content Mining Authors: Murray-Rust, Peter Abstract: Abstract— We present evidence that content-mining of scholarly articles is now technically feasible and highly valuable both. However researchers and information technologist are blocked by legal and contractual barries from using it and developing the methodologies. We review the problems and propose changes in legal policy which we have already submitted to the UK's Hargreaves report on intellectual property reform. We put forward the fundamental rights of scholars and embed them in a manifesto: "The right to read is the right to mine", "Users and providers should encourage machine processing, and "Facts don't belong to anyone". Description: Conference for the Fellows of OpenForum Academy - 24th September 2012 Brussels

A computational analysis of the vibrational absorption of molecular solids in the teraherz range

Mon, 02 Jul 2012 23:00:00 GMT

Title: A computational analysis of the vibrational absorption of molecular solids in the teraherz range Authors: Tomerini, Daniele Abstract: In this thesis, we deal with the application of transmission terahertz spectroscopy as an analysis tool for the study of molecular solids, in particular organic crystals of pharmaceutical interest. Most of the work has been performed using two computational packages aimed at the interpretation of the spectra, one based on molecular forcefields (DMACRYS), the other on solid state density functional theory (CASTEP). We compare low temperature determinations of several molecular organic crystals to calculated spectra, and attempt to assign calculated modes of vibrations to absorption peaks, based on the similarity in frequency between the measured and calculated peaks. One of the main aims of this work is to establish the limits of our forcefield approach, which is based on the approximation that the intramolecular degrees of freedom can be neglected. We analyse the normal modes of vibration calculated with CASTEP, evaluating the amount of rigid molecule rotational and translational contribution to each eigenvector as a function of frequency, in order to validate our forcefield approach. We also compare the two sets of eigenvectors from the DMACRYS and CASTEP calculations to assess the similarity between the two approaches. We perform the same eigenvectors analysis on several hydrate systems in order to understand the role of water in the lattice dynamics of crystalline hydrates. We attempt a classification of the eigenvectors based on the strength of the forces involved in the molecular vibrations and based on the amount of the water contribution to each normal mode. A set of isostructural crystals is analysed in order to understand the effect that small variations (in the molecular formula and in the unit cell arrangement) have on the measured and calculated absorption spectra of a crystal. Finally, we discuss the use and development of computational methods that allow us to have a more realistic description of the molecular electrostatic in DMACRYS.

Extending the boundaries of the usage of NMR chemical shifts in deciphering biomolecular structure and dynamics

Mon, 02 Jul 2012 23:00:00 GMT

Title: Extending the boundaries of the usage of NMR chemical shifts in deciphering biomolecular structure and dynamics Authors: Sahakyan, Aleksandr B. Abstract: NMR chemical shifts have an extremely high information content on the behaviour of macromolecules, owing to their non-trivial dependence on myriads of structural and environmental factors. Although such complex dependence creates an initial barrier for their use for the characterisation of the structures of protein and nucleic acids, recent developments in prediction methodologies and their successful implementation in resolving the structures of these molecules have clearly demonstrated that such barrier can be crossed. Furthermore, the significance of chemical shifts as useful observables in their own right has been substantially increased since the development of the NMR techniques to study low populated "excited" states of biomolecules. This work is aimed at increasing our understanding of the multiple factors that affect chemical shifts in proteins and nucleic acids, and at developing high-quality chemical shift predictors for atom types that so far have largely escaped the attention in chemical shift restrained molecular dynamics simulations. A general approach is developed to optimise the models for structure-based chemical shift prediction, which is then used to construct CH3Shift and ArShift chemical shift predictors for the nuclei of protein side-chain methyl and aromatic moieties. These results have the potential of making a significant impact in structural biology, in particular when taking into account the advent of recent techniques for specific isotope labelling of protein side-chain atoms, which make large biomolecules accessible to NMR techniques. Through their incorporation as restraints in molecular dynamics simulations, the chemical shifts predicted by the approach described in this work create the opportunity of studying the structure and dynamics of proteins in a wide range of native and non-native states in order to characterise the mechanisms underlying the function and dysfunction of these molecules.

Ring-polymer approaches to instanton theory

Mon, 02 Jul 2012 23:00:00 GMT

Title: Ring-polymer approaches to instanton theory Authors: Richardson, Jeremy O. Abstract: Inspired by the success of the ring-polymer molecular dynamics (RPMD) method, we derive a transition-state-theory version (RPTST) with a dividing surface which is, in general, conical in ring-polymer space. It is explained why this conical form is a good approximation to the optimal dividing surface and therefore why centroid-based quantum transition-state theories are inaccurate for asymmetric barriers at low temperatures. The geometry of the ring-polymer transition state is found to describe a finite-difference approximation to the semi-classical instanton trajectory (a classical periodic orbit of length βħ on the inverted potential). Based on this, a new practical method for locating multidimensional instantons is proposed, by computing saddle points on the ring-polymer surface, and a derivation for the reaction rate constant based on the "ImF" premise using the ring-polymer formalism is shown to be far simpler than in previous instanton approaches based on functional determinants. The resulting expression is based only on the ring-polymer potential at the transition-state and its Hessian, and is applied to evaluate the rate in a number of polyatomic systems. We show that a free-energy version of the ImF instanton theory is related to RPTST and thereby provide an explanation for why RPMD produces accurate results for thermal reaction rates in the deep-tunnelling regime and demonstrate how it can be made more efficient and systematically improved. From this, we also explain why RPMD is seen to underestimate the rates of symmetric reactions and overestimate the rates of asymmetric reactions. We also present a ring-polymer instanton derivation of a theory for calculating tunnelling splittings leading to another new practical method, which owing to its simple form, is easily extended to determine the entire tunnelling-splitting pattern of molecular clusters with two or more degenerate wells. This method is applied to the water dimer, trimer, and octamer, and shown to be in good overall agreement with experiment and to provide a deeper understanding of the tunnelling pathways.

Studies of urban air quality using electrochemical based sensor instruments

Mon, 02 Jul 2012 23:00:00 GMT

Title: Studies of urban air quality using electrochemical based sensor instruments Authors: Popoola, Olalekan Abdul Muiz Abstract: Poor air quality has been projected to be the world’s top cause of environmental premature mortality by 2050 surpassing poor sanitation and dirty water (IGBP / IGAC press release, 2012 ). One of the major challenges of air quality management is how to adequately quantify both the spatial and temporal variations of pollutants for the purpose of implementing necessary mitigation measures. The work described in this thesis aims to address this problem using novel electrochemical based air quality (AQ) sensors. These instruments are shown to provide cost effective, portable, reliable, indicative measurements for urban air quality assessment as well as for personal exposure studies. Three principal pollutants CO, NO and NO2 are simultaneously measured in each unit of the AQ instrument including temperature / RH measurements as well as GPS (for time and position) and GPRS for data transmission. Laboratory studies showed that the electrochemical sensor nodes can be highly sensitive, showing linear response during calibration tests at ppb level (0-160 ppb). The instrumental detection limits were found to be < 4 ppb (CO and NO) and < 1 ppb for NO2 with fast response time equivalent to t90 < 20 s. Several field studies were carried out involving deployment of both the mobile and static electrochemical sensor nodes. Results from some short-term studies in four different cities including Cambridge (UK), London (UK), Valencia (Spain) and Lagos (Nigeria) are presented. The measurements in these cities represent snapshot of the pollution levels, the stark contrast between the pollution level especially CO (mean mixing ratio of 16 ppm over 3 hrs) in Lagos and the other three cities is a reflection of the poor air quality in that part of the world. Results from long-term AQ monitoring using network of 46 static AQ sensors were used to characterise pollution in different environments ranging from urban to semi-urban and rural locations. By coupling meteorological information (wind measurements) with pollution data, pollution sources, and phenomena like the street canyon effect can be studied. Results from the long-term study also revealed that siting of the current fixed monitoring stations can fail to represent the actual air quality distribution and may therefore be unrepresentative. This work has shown the capability of electrochemical based AQ sensors in complementing the existing fixed site monitors thus demonstrating an emerging measurement paradigm for air quality monitoring and regulation, source attribution and human exposure studies.

Winnow based identification of potent hERG inhibitors in silico: comparative assessment on different datasets

Mon, 30 Apr 2012 23:00:00 GMT

Title: Winnow based identification of potent hERG inhibitors in silico: comparative assessment on different datasets Description: RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.

Molecular dynamics simulations and docking of non-nucleoside reverse transcriptase inhibitors (NNRTIs): a possible approach to personalized HIV treatment

Mon, 30 Apr 2012 23:00:00 GMT

Title: Molecular dynamics simulations and docking of non-nucleoside reverse transcriptase inhibitors (NNRTIs): a possible approach to personalized HIV treatment Description: RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.

Probabilistic classifier: generated using randomised sub-sampling of the feature space

Mon, 30 Apr 2012 23:00:00 GMT

Title: Probabilistic classifier: generated using randomised sub-sampling of the feature space Description: RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.

Self-assembly of synthetic and biological components in water using cucurbit[8]uril

Tue, 07 Feb 2012 00:00:00 GMT

Title: Self-assembly of synthetic and biological components in water using cucurbit[8]uril Authors: Zayed, Jameel Majed Abstract: This thesis discusses progress made towards assembling molecular building blocks in the presence of our molecular host of choice, cucurbit[8]uril (CB[8]). Our studies on the self-assembly of synthetic and biological components in water bridge overlapping concepts and techniques drawn from the fields of synthetic organic chemistry, supramolecular self-assembly, and applied NMR techniques. Chapter 1 introduces the reader to chemical complexity, and how supramolecular chemists have advanced in their capability of assembling more complex molecular architectures. The discussion focusses particularly on self-assembly carried out in the aqueous phase, and how, like in biology, molecular design of the building blocks become critical in enabling non-covalent assembly to occur in this dynamic, and relatively competitive environment. The cucurbit[n]uril family of molecular hosts are then introduced with an overview of their modes of binding, and affinities towards typical guests. Finally, a practical introduction to NMR methods gaining prominence in supramolecular chemistry is presented. In particular, the use of diffusion NMR, a key tool for probing the solution dynamics of molecular assemblies, is highlighted. Chapter 2 details work carried out on the CB[8]-mediated self-assembly of supramolecular block copolymers from polymeric, and small molecule building blocks. Here, end group-functionalised polymer guests were shown to assemble with small molecule ditopic guests in the presence of CB[8] to form block copolymers. Copolymers of various molecular weights were assembled, and the supramolecular complexes were studied using solution viscometry and diffusion NMR. This study represented the first use of diffusion NMR for probing the assembly of polymeric guests with CB[8]. Chapter 3 describes the self-assembly of CB[8] with complementary ditopic guests. High molecular weight supramolecular polymers are known to form through the step-growth assembly of complementary ditopic building blocks. Here we sought to probe CB[8]’s ability to drive supramolecular polymerisation. Solution viscometry, ESI-MS, and diffusion NMR were used to investigate the self-assembly process, which indicated that cyclic oligomers had formed. The relatively low solubility of CB[8] in water was thought to be a major limitation to polymer formation in this instance. Important observations relating to the effect of salts on the solution viscosities and stabilities of the complexes, are also discussed. Chapter 4 places emphasis on the synthetic methods employed towards preparing multivalent guests for CB[8] binding studies. Our synthetic guests were based on watersoluble oligomers of ethylene glycol. A bidirectional elongation route is presented for accessing higher molecular weight, and monodisperse ethylene glycol oligomers (n = 12) in suitable purity. Chapter 5 describes the assembly of protein-polymer conjugates, and the versatility of diffusion NMR as a means to probe the assembly process. Here, end group-functionalised poly(ethylene glycol) guests were appended to bovine serum albumin (BSA) through a mixed chemical ligation-self assembly protocol. The NMR studies conducted are emphasised here, which served to complement other characterisation methods used that are reported elsewhere. Chapter 6 discusses ongoing work on lipid-based guests, and the resulting liposome assemblies formed. Head group-functionalised phospholipid guests, and cholesterol-based guests were synthesised. Phospholipid guests were obtained through an enzymatic route, a novelty in our group. Dye-encapsulated liposomes were then assembled, purified, and characterised by fluorescence microscopy. Finally, we sought to optimise lipid formulations to enhance liposome stability, towards conducting molecular recognition studies in the presence of CB[8]. Chapter 7 then closes the thesis with concluding remarks that summarise the described research, while highlighting points of note.

Predicting the mechanism of phospholipidosis

Thu, 26 Jan 2012 00:00:00 GMT

Title: Predicting the mechanism of phospholipidosis Authors: Lowe, Robert; Mussa, Hamse Y; Nigsch, Florian; Glen, Robert C; Mitchell, John BO Abstract: Abstract The mechanism of phospholipidosis is still not well understood. Numerous different mechanisms have been proposed, varying from direct inhibition of the breakdown of phospholipids to the binding of a drug compound to the phospholipid, preventing breakdown. We have used a probabilistic method, the Parzen-Rosenblatt Window approach, to build a model from the ChEMBL dataset which can predict from a compound's structure both its primary pharmaceutical target and other targets with which it forms off-target, usually weaker, interactions. Using a small dataset of 182 phospholipidosis-inducing and non-inducing compounds, we predict their off-target activity against targets which could relate to phospholipidosis as a side-effect of a drug. We link these targets to specific mechanisms of inducing this lysosomal build-up of phospholipids in cells. Thus, we show that the induction of phospholipidosis is likely to occur by separate mechanisms when triggered by different cationic amphiphilic drugs. We find that both inhibition of phospholipase activity and enhanced cholesterol biosynthesis are likely to be important mechanisms. Furthermore, we provide evidence suggesting four specific protein targets. Sphingomyelin phosphodiesterase, phospholipase A2 and lysosomal phospholipase A1 are shown to be likely targets for the induction of phospholipidosis by inhibition of phospholipase activity, while lanosterol synthase is predicted to be associated with phospholipidosis being induced by enhanced cholesterol biosynthesis. This analysis provides the impetus for further experimental tests of these hypotheses. Description: RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.

Dynamic combinatorial synthesis of donor-acceptor catenanes

Tue, 10 Jan 2012 00:00:00 GMT

Title: Dynamic combinatorial synthesis of donor-acceptor catenanes Authors: Cougnon, Fabien B. L. Abstract: Dynamic combinatorial chemistry (DCC) is a powerful method for synthesising complex molecules and identifying unexpected receptors. Chapter 1 gives an overview of the concept of DCC and its applications, and discusses its evolution to date. Chapter 2 describes the discovery of a new generation of donor-acceptor [2]catenanes in aqueous dynamic combinatorial systems. The assembly of these [2]catenanes is promoted by a high salt concentration (1 M NaNO3), which raises the ionic strength and encourages hydrophobic association. More importantly, a mechanism that explains and predicts the structures formed is proposed, giving a fundamental insight into the role played by hydrophobic effect and donor-acceptor interactions in this process. Building on these results, Chapter 3 describes the assembly in high salt aqueous libraries of a larger structure: a [3]catenane. Remarkably, the [3]catenane exhibits strong binding interactions with a biologically relevant target – spermine – in water under near-physiological conditions. Its synthesis is improved if the salt is replaced by a sub-mM concentration of spermine, acting as a template. Chapter 4 explores in further detail how subtle variations in the building block design influence the selective formation of either [2] or [3]catenanes. This last section underlines both the advantages and the limitations of the method developed in Chapter 3. After a short conclusion (Chapter 5), Chapter 6 gives experimental details.

CML: Evolution and Design

Thu, 13 Oct 2011 23:00:00 GMT

Title: CML: Evolution and Design Authors: Murray-Rust, Peter; Rzepa, Henry S Abstract: Abstract A retrospective view of the design and evolution of Chemical Markup Language (CML) is presented by its original authors. Description: RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.

On the use of CML in computational materials research

Thu, 12 Jan 2012 00:00:00 GMT

Title: On the use of CML in computational materials research Authors: Murray-Rust, Peter; Dove, Martin

Service-oriented science: why good code matters for science and why a fundamental change in thinking is required

Thu, 12 Jan 2012 00:00:00 GMT

Title: Service-oriented science: why good code matters for science and why a fundamental change in thinking is required Authors: Murray-Rust, Peter; Neylon, Cameron

Applied and Implied Semantics in Crystallographic Publishing

Thu, 12 Jan 2012 00:00:00 GMT

Title: Applied and Implied Semantics in Crystallographic Publishing Authors: Murray-Rust, Peter; McMahon, Brian

Why PNNL are supporting semantic science - Data at EMSL/PNNL

Thu, 12 Jan 2012 00:00:00 GMT

Title: Why PNNL are supporting semantic science - Data at EMSL/PNNL Authors: Murray-Rust, Peter; Shelton, William

CMLisation of NWChem and development strategy for FoXification and dictionaries

Thu, 12 Jan 2012 00:00:00 GMT

Title: CMLisation of NWChem and development strategy for FoXification and dictionaries Authors: Murray-Rust, Peter; de Jong, Bert