Agency: GTR | Branch: EPSRC | Program: | Phase: Fellowship | Award Amount: 488.45K | Year: 2016
Advances in High Performance Computing (HPC) and scientific software development will have increasingly significant societal impact through the computational design of new products, medicines, materials and industrial processes. However, the complexity of modern HPC hardware means that scientific software development now requires teams of scientists and programmers to work together, with different and non-overlapping skill-sets required from each member of the group. This complexity can lead to software development projects stalling. Investments in software development are in danger of being lost, either because key members of a team move on, or because a lack of planning or engagement means that a sustainable user and developer community has failed to gel around a particular code. Research Software Engineers (RSEs) can solve this problem. RSEs have the skills and training necessary to support software development projects as they move through different stages of the academic software lifecycle. Academic software evolves along this lifecycle, from being a code used by an initial team of researchers, through to a large multi-site community code used by academics and industrialists from across the UK and around the World. RSEs provide the training and support needed to help academic software developers structure their projects to support the sustainable growth of their user and developer communities. RSEs are also highly skilled programmers who can train software developers in advanced HPC techniques, and who can support developers in the implementation, optimisation and testing of complex and intricate code. Together with academic software developers, RSEs can support UK investment in HPC, and ensure that the potential of computational science and engineering to revolutionise the design of future products and industrial processes is realised. This project aims to develop sustainable RSE career pathways and funding at Bristol. This will support the growth of a sustainable team of RSEs at the University. Software development projects that will be supported include; the building of code to interface real biological cells with virtual simulated cells, so to support the rapid design of new biomanufacturing control processes; the development of code to more quickly model the behaviour of electrons in novel materials, to support the design of new fuel cells and batteries; code to improve our understanding of glass-like matter, so to help design new materials with exciting new properties; software to support modelling of the quantum interaction between laser light and microscopic nanoparticles, to support the design of optical tweezers and new optically driven nanomachines; and code to design new medicinal drugs and to understand why existing treatments are no longer working, thereby supporting the development of 21st century medicine. Finally, this project aims to create a coherent set of teaching materials in programming and research software engineering. These, together with the development of software to support science and programming lessons held in an interactive 3D planetarium, will help inspire and educate the next generation of scientists and RSEs. These materials will showcase how maths, physics, computing and chemistry can be used in the real world to create the high-tech tools and industries of the future.
Hussain A.,University of Nottingham |
Melville J.L.,Cresset BioMolecular Discovery Ltd. |
Hirst J.D.,University of Nottingham
Journal of Computer-Aided Molecular Design | Year: 2010
Actin-binding natural products have been identified as a potential basis for the design of cancer therapeutic agents. We report flexible docking and QSAR studies on aplyronine A analogues. Our findings show the macrolide 'tail' to be fundamental for the depolymerisation effect of actin-binding macrolides and that it is the tail which forms the initial interaction with the actin rather than the macrocycle, as previously believed. Docking energy scores for the compounds were highly correlated with actin depolymerisation activity. The 3D-QSAR models were predictive, with the best model giving a q 2 value of 0.85 and a r 2 of 0.94. Results from the docking simulations and the interpretation from QSAR "coeff*stdev" contour maps provide insight into the binding mechanism of each analogue and highlight key features that influence depolymerisation activity. The results herein may aid the design of a putative set of analogues that can help produce efficacious and tolerable anti-tumour agents. Finally, using the best QSAR model, we have also made genuine predictions for an independent set of recently reported aplyronine analogues. © 2009 Springer Science+Business Media B.V.
Calero C.S.,University of Sheffield |
Farwer J.,University of Sheffield |
Gardiner E.J.,University of Sheffield |
Hunter C.A.,University of Sheffield |
And 4 more authors.
Physical Chemistry Chemical Physics | Year: 2013
A liquid is composed of an ensemble of molecules that populate a large number of different states, so calculation of the solvation energy of a molecule in solution requires a method for summing the interactions with the environment over all of these states. The surface site interaction model for the properties of liquids at equilibrium (SSIMPLE) simplifies the surface of a molecule to a discrete number of specific interaction sites (SSIPs). The thermodynamic properties of these interaction sites can be characterised experimentally, for example, through measurement of association constants for the formation of simple complexes that feature a single H-bonding interaction. Correlation of experimentally determined solution phase H-bond parameters with gas phase ab initio calculations of maxima and minima on molecular electrostatic potential surfaces (MEPS) provides a method for converting gas phase calculations on isolated molecules to parameters that can be used to estimate solution phase interaction free energies. This approach has been generalised using a footprinting technique that converts an MEPS into a discrete set of SSIPs (each described by a polar interaction parameter, εi). These SSIPs represent the molecular recognition properties of the entire surface of the molecule. For example, water is described by four SSIPs, two H-bond donor sites and two H-bond acceptor sites. A liquid mixture is described as an ensemble of SSIPs that represent the components of the mixture at appropriate concentrations. Individual SSIPs are assumed to be independent, so speciation of SSIP contacts can be calculated based on properties of the individual SSIP interactions, which are given by the sum of a polar (εiε j) and a non-polar (EvdW) interaction term. Results are presented for calculation the free energies of transfer of a range of organic molecules from the pure liquid into water, from the pure liquid into n-hexadecane, from n-hexadecane into water, from n-octanol into water, and for the transfer of water from pure water into a range of organic liquids. The agreement with experiment is accurate to within 1.6-3.9 kJ mol-1 root mean square difference, which suggests that the SSIMPLE approach is a promising method for estimation of solvation energies in more complex systems. © 2013 the Owner Societies.
Cheeseright T.J.,Cresset BioMolecular Discovery Ltd. |
Mackey M.D.,Cresset BioMolecular Discovery Ltd. |
Scoffin R.A.,Cresset BioMolecular Discovery Ltd.
Current Computer-Aided Drug Design | Year: 2011
The question of how and why a small molecule binds to a protein is central to ligand-based drug discovery. The traditional way of approaching these questions is pharmacophore analysis. However, pharmacophores as usually applied lack quantitation and subtlety. An improvement is to consider the electrostatic and steric fields of the ligand directly. Molecular fields provide a rich view of the potential interactions that a molecule can make and can be validated through experimental data on molecular interactions and through quantum mechanics calculations. A technique is presented in this review for comparing molecules using molecular fields and assigning similarity scores. This high information content method can be used to align molecules for SAR analysis, to determine the bioactive conformation from ligand data, and to screen large libraries of compounds for structurally unrelated actives. An extension to allow interactive exploration of chemistry space via bioisostere analysis is also reviewed. Examples from the literature showing the success of these methods are presented, and future directions discussed. © 2011 Bentham Science Publishers Ltd.
Agency: GTR | Branch: Innovate UK | Program: | Phase: Collaborative Research & Development | Award Amount: 330.38K | Year: 2011
The project aims to create a platform through which the partners are able to offer products and services to customers in the area of drug re-profiling or re-purposing. Re-profiling generally consists of looking for a new therapeutic application for an existing drug molecule, or stated another way, searching databases of known drug molecules to find compounds which have high similarity to a query structure of interest. Cresset and Biolauncher bring together skills in computational chemistry, large-scale textual informatics and semantic data integration to create a system which enables the provision of applications and services in such re-profiling exercises to life sciences customers.
Cresset Biomolecular Discovery Ltd. | Date: 2014-04-09
The present invention provides Nalidixic acid and analogues of Nalidixic acid, and methods for treating inflammatory disorders. The Nalidixic acid and analogues of Nalidixic acid may be formulated for topical delivery or systemic delivery. The inflammatory disorders that may be treated with the Nalidixic acid and analogues of Nalidixic acid include respiratory diseases, chronic degenerative diseases, dematological conditions, chronic demyelinating diseases, dental diseases, ophthalmic conditions, inflammatory bowel diseases, and graft versus host diseases.
Cresset Biomolecular Discovery Ltd | Date: 2014-04-09
The present invention provides Nalidixic acid and analogues of Nalidixic acid, pharmaceutical compositions including at least one of Nalidixic acid and analogues of Nalidixic acid, and methods for treating inflammatory ophthalmic disorders by local administration. The ophthalmic disorders may be characterized by ocular inflammation, dry eye disorders, pathological ocular angiogenesis, or retinal or sub-retinal edema.
Market research to validate the commercial potential for a novel application that connects a multi-platform GUI to cloud-based infrastructure, to enable the rational structurebased design of new compounds for pharmaceutical R&D
Agency: GTR | Branch: Innovate UK | Program: | Phase: Smart - Proof of Market | Award Amount: 25.00K | Year: 2015
The availability of crystallographic information for protein targets of pharmaceutical interest has dramatically increased in the recent years, even for those targets, such as Trans-membrane Receptors and Ion Channels, which until recently were considered extremely hard to crystallise. The availability and cost of high-performing computing through cloud-based infrastructure has also dramatically improved in the recent years. This has made the application of complex drug design methods and algorithms to the study of complex targetligand interactions accessible to pharmaceutical researchers. Cresset have an existing suite of software tools aimed at helping both computational and medicinal chemists with the design and synthesis of molecules, particularly helping with the understanding of the 3D properties of the molecules and their interactions with target proteins; however it is our belief that there is an increasing need for new tools to facilitate a rapid utilization of cloud-resources in platform-independent desktop applications. We intend to carry out market research in this area to validate our belief that a new software application, that integrates cloud resources with a traditional interactive GUI for structurebased design, will provide a paradigm shift in the speed of new molecule design and in the exploitation of available crystallographic information on protein targets of pharmaceutical interest. We believe there is a significant worldwide market opportunity for such a tool, but we strongly need to validate our concept with broader market data than we have been able to access from our current customer contacts.
Agency: GTR | Branch: Innovate UK | Program: | Phase: Smart - Development of Prototype | Award Amount: 136.10K | Year: 2016
The availability of crystallographic information for protein targets of pharmaceutical interest has dramatically increased in the recent years, even for those targets, such as trans-membrane receptors and ion channels, which until recently were considered extremely hard to crystallise. The availability and cost per calculation of high-performing computing through cloud-based infrastructure has also dramatically improved in the recent years. This has made the application of complex drug design methods and algorithms to the study of target-ligand interactions accessible to many more pharmaceutical researchers. Cresset have an existing set of products aimed at helping both computational and medicinal chemists with the design of molecules, calculating the 3D properties of molecules and their interactions with target proteins. There is a constant desire for new tools and scientific methods to facilitate the design process. As new methods are often highly compute intensive, these are ideally presented to researchers through cloud computing. We have carried out market research in this area and have received very positive feedback on our concept for a new software application that integrates cloud resources with a traditional interactive GUI for structure-based design. The market feedback also indicates that a cloudbased platform will become increasingly valuable over the next few years as a means of providing rapid access to novel science. Our research indicates that an application that combines this novel architecture with cutting edge science will provide a paradigm shift in the speed of new molecule design and in the exploitation of available crystallographic information on protein targets of pharmaceutical interest.
Agency: GTR | Branch: Innovate UK | Program: | Phase: Smart - Proof of Market | Award Amount: 25.00K | Year: 2015
Outsourcing of chemical synthesis is the backbone of the modern paradigm for pharmaceutical R&D, particularly in the early discovery phase of a project. This has meant a radical change in terms of the composition of Pharma R&D teams, where in the past there would have been a large team of chemists supporting each project, there is now one or two senior chemists who function as molecule designers, who are backed up by remote teams (often in India, China or other low-cost locations) responsible for the synthesis of the designed molecules. Cresset have an existing suite of software tools aimed at helping both computational and medicinal chemists with the design and synthesis of molecules, particularly helping with the understanding of the 3D properties of the molecules and their interactions with target proteins; however it is our belief that with the new paradigm there is an increasing need for new tools to facilitate project communication and speed up the delivery of new molecules. We intend to carry out market research in this area to validate our belief that a new software application, based on a cloud platform and delivering 3D design capability, plus 2D structural entry and representation, will meet the needs of the senior scientists designing the molecules, the outsource synthesis teams making the molecules, and the other members of the project team who rely on getting access to the structures and related information in an easy and timely manner. We intend to further validate the market opportunity for both a secure public cloud application and an internally hosted private cloud application, which would appeal more to large Pharma customers (the former appealing to academics and smaller companies). We believe there is a significant worldwide market opportunity for such a tool, but we strongly need to validate our concept with broader market data than we have been able to access from our current customer contacts.