Insights into Mode of Action & Prioritisation of HTS Data

Brad Sherborne, Schering-Plough, Head of CMC

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Launch presentation

About the speaker

Brad Sherborne graduated from the University of East Anglia, Norwich with a PhD in Theoretical Chemistry and took two Post-doctoral positions in High Energy Physics (University of Canterbury, New Zealand and Imperial College, London) before joining Hoffman la Roche as a Computational Chemist. Brad has experiences of working in multiple stages of drug discovery with many different protein targets and therapeutic areas. Brad has led teams of computational scientists at large, medium and biotech pharmaceutical companies. He maintains an interest in computational techniques to maximise the quality and information gained in HTS and used by medicinal chemists to guide compound design.

Abstract

Fragment based drug discovery (FBDD) is gaining momentum for enzyme targets with a tractable crystallographic system in place. The determination of the high resolution crystal structure of the target :: fragment complex is a key step in every FBDD program as it serves as the basis for fragment hit optimization by principles of structure based drug design. We report herein on our results obtained from a FBDD program directed against the MAPKAP kinase 2 (MK2), an attractive inflammation target downstream of p38a and upstream of tumor necrosis factor alpha (TNFa) mRNA translation. We have completed diverse fragment screens and fragment hit confirmation by high-concentration biochemical assays and nuclear magnetic resonance (NMR). We have further confirmed some of the fragment hits for cellular activity in a macrophage based TNFa secretion assay. MK2 is known to be a challenging target for crystallography and all structures reported to date are of moderate resolution only. In order to use crystallography for driving medicinal chemistry optimization of MK2 inhibitors we set out to improve the crystallographic resolution by MK2 mutant design and insect cell expression. The presentation will detail the latest status of this ongoing research program.

Launch presentation