Novartis Horsham Research Centre
Horsham, West Sussex
Presentations
- Krisztina Boda (Leeds University, UK)
SynSPROUT: A tool for generating synthetically accessible ligands by De Novo design [Slides] [Abstract] - Michael Briggs (Leeds University, UK)
Design and Synthesis of Novel Paraherquamide Analogues as Potential Endectocides [Slides] [Abstract] - Ulrich Dauer (4SC AG, Muenchen, Germany)
The Challenges of Virtual Screening - Peter Ertl (Novartis, Basel, Switzerland)
Enhancement of hit rate in high throughput screening by using fragment-based substructure analysis [Slides] [Abstract] - Mike Hann (GlaxoSmithKline, Stevenage, UK)
What makes a good lead? [Slides] [Abstract] - Jerry Lanfear (Pfizer, Sandwich, UK)
The completion of the genome and it’s significance for Drug Discovery [Abstract] - Peter Lockey (Argenta Discovery, Harlow, Essex, UK)
Assay Design and Quality Control in HTS and Lead Optimisation [Slides] [Abstract] - Stephen Pickett (Roche Discovery, Welwyn, UK)
Establishing a Successful Virtual Screening Strategy [Slides] [Abstract]
Abstracts
Presentation: Krisztina Boda
SynSPROUT: A tool for generating synthetically accessible ligands by De Novo design
Leeds University, UK [Slides]
One of the insufficiencies of De Novo molecular structure design programs is that after a time and memory consuming structure generation process, many of the solutions produced may not be synthetically accessible.
Our aim to eliminate this deficiency by enhancing the well-known molecular structure design program SPROUT which has been developed in the University of Leeds since 1992. SynSPROUT is a new variant of SPROUT, which builds synthetic constraints into the structure generation process by starting with a library of readily available starting materials, and then joining these together in a way that corresponds exactly to chemical reactions from a user modifiable knowledge base.
A key feature of this new version is an automatic method for the generation of large starting 3D fragment libraries. In one variant, drug-like structures are taken back to their starting materials using a user-defined retro-synthetic knowledge base. These starting materials can then be used as building blocks in the initial docking and ligand building process. The library generation process also provides perception of essential atom properties such as hydrogen bonding and hybridisation with functional group detection.
The presentation will provide an overview of the main concepts and then focus on the methodology involved in the automatic process of building a fragment library together with examples of fragmentation of the MDL MDDR database to build libraries for De Novo drug design.
Presentation: Michael Briggs
Design and Synthesis of Novel Paraherquamide Analogues as Potential Endectocides
Leeds University, UK [Slides]
Nematode parasites are known to cause serious morbidity and mortality in both humans and animals. The paraherquamide family of natural products have the potential to yield new treatments for nematodal diseases. They have been shown to paralyse worms present in the intestines of infected animals, including nematode populations that are resistant to current anthelmintic drugs. SAR studies on paraherquamide A, (see figure), the most potent member of the paraherquamide family, suggest that the essential functionality for significant activity is the oxindole portion of the molecule, the basic nitrogen, 14-methyl group, and the hydrophobic region of the dioxepin ring.
Using SPROUT, a de novo ligand design program developed at Leeds University, it is possible to design molecules which fit the constraints of the pharmacophore hypothesis. Initial work has focussed on the pharmacophore comprising the oxindole moiety and the basic nitrogen. A number of molecules generated by SPROUT have been synthesised and their biological activity assessed. Three of the compounds were found to have Ki values less than 10 uM.
Presentation: Ulrich Dauer
The Challenges of Virtual Screening
4SC AG, Muenchen, Germany
HASH(0x34eaefc)
Presentation: Peter Ertl
Enhancement of hit rate in high throughput screening by using fragment-based substructure analysis
Novartis, Basel, Switzerland [Slides]
High-throughput screening techniques applied nowadays routinely in pharma industry are able to process very large number of potential drug candidates. But the number of molecules available for screening is even larger – several millions samples are available from various commercial sources in addition to hundreds of thousands available in in-house archives of large pharma and agro companies. And thank to the combinatorial chemistry this number is growing rapidly. To “find the nuggets”, i.e. to identify potentially active molecules from this large pool, is therefore not a trivial task.
Various strategies are used to select putative active molecules for screening. These are based on the physico-chemical properties, identification of active substructures, or virtual docking to the target’s binding site. In the present study we focus on the application of fragment-based substructure analysis for enhancement of hit rate in high throughput screening.
Substructure analysis is based on an assumption that some fragments present in molecule increase the likelihood of biological activity, while others have negative effect on activity. The method is therefore based on the analysis of distribution of fragments between a training set of active and inactive molecules. In a training cycle an “activity contribution” is assigned to each fragment, based on its distribution between these two sets. The activity of new molecule may be then estimated by summing up contributions of all fragments in the molecule. This gives us possibility to rank candidates for screening and test only molecules with reasonable theoretical activity.
The performance of fragment-based substructure analysis will be demonstrated in an in-silico screening experiment of publicly available NCI HIV data. The method provides up to 20-fold enhancement of hit rate in comparison with random selection of molecules for screening.
Presentation: Mike Hann
What makes a good lead?
GlaxoSmithKline, Stevenage, UK [Slides]
Using a simple model of ligand-receptor interactions, the interactions between ligands and receptors of varying complexities have been studied and the probabilities of binding calculated. It is observed that as the systems become more complex the chance of observing a useful interaction for a randomly chose ligand falls dramatically. The implication of this for the design of combinatorial libraries is explored. A large set of drug leads and optimised compounds is profiled using several different properties relevant to molecular recognition. The changes observed for these properties during the drug optimisation phase support the hypothesis that less complex molecules are more common starting points for the discovery of drugs. An example of the use of simple molecules for directed screening for thrombin inhibitors will be presented.
Presentation: Jerry Lanfear
The completion of the genome and it’s significance for Drug Discovery
Pfizer, Sandwich, UK
The completion of the human genome represents the summation of over 10 years of global effort and investment spread across multiple publicly and privately funded institutions. It’s also a significant landmark in our understanding of human biology and also, potentially, for our future drug discovery output. This presentation will present a view of the human genome from a specifically drug discovery perspective to try and shed some light on how this huge set of information and opportunities may impact upon our future productivity and success.
Presentation: Peter Lockey
Assay Design and Quality Control in HTS and Lead Optimisation
Argenta Discovery, Harlow, Essex, UK [Slides]
Despite the revolution in assay technologies used in HTS and Lead Optimisation, quality control of the data generated is still the essential factor for the success of a project. The acceptance criteria for assays in these two phases of drug discovery will be discussed, together with data quality control, the problems that often arise in the development and running of biological screens, and their implications for the Medicinal Chemist.
Presentation: Stephen Pickett
Establishing a Successful Virtual Screening Strategy
Roche Discovery, Welwyn, UK [Slides]
Virtual screening is a vital tool in modern lead identification processes. The implementation of virtual screening at Roche Discovery Welwyn will be discussed through reference to proprietary drug discovery projects. In particular, the application to the discovery of low molecular weight enzyme inhibitors via virtual needle screening will be described.