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Continued from page 56


8 Jones, PS, McElroy, S, Morrison, A, Pannifer, A. Future Med. Chem., 2015, 7(14) 1847- 1852. 9 Ellis, J. Biocompare, https://www.biocompare.com/ Editorial-Articles/359206- New-Trends-in-Compound- Management/. 10 McElroy, SP, Jones, PS, Barrault, DV. Drug Discovery Today, 2017, 22(2), 199-203. DOI: 10.1016/j.drudis. 2016.09.028. 11 Giordanetto, F, Jones, P, Nelson, A, Benningshof, J, Muller, G, Pannifer, A, van Boeckel, S, Tzalis, D. Comprehensive Medicinal Chemistry III, Chapter 1.18, 505-519; Eds. S. Chackalamannil, D. Rotella, S. Ward; Oxford: Elsevier; 2017. 12 Baell, J, Walters, MA. Nature, 2014, 513, 481-483. 13 Morreale, FE, Testa, A, Chaugule, VK, Bortoluzzi, A, Ciulli, A, Walden, H. J. Med. Chem., 2017, 60, 8183-8191. 14 McGovern, SL, Caselli, E, Grigorieff, N, Shoichet, BK, J. Med. Chem., 2002, 45, 1712- 1722. 15 Blevitt, JM, Hack, MD, Herman, KL, Jackson, PF, Krawczuk, PJ, Lebsack, AD, Liu, AX, Mirzadegan, T, Nelen, MI, Patrick, AN, Steinbacher, S, Milla, ME, Lumb, KJ, J. Med. Chem., 2017, 60, 3511-3517. 16 Baillie, G, Morrison, A, McElroy, S. 6th Novalix Conferences – Biophysics in Drug Discovery, March 20-22, 2019. 17 Paillard, G, Cochrane, P, Jones, PS, van Hoorn, WP, Caracoti, A, van Vlijmen, H, Pannifer, AD. Drug Discovery Today, 2016, 21(1), 97-102.


but our focus was naturally drawn to the six hits that acted in a similar manner to the reference com- pound. This also resulted in an enhancement to the robustness set to include a library of common salts and likely contaminants from synthesis, metals etc, which are now routinely screened during assay development (in orthogonal biophysical assays as well as primary biochemical assays).


Identifying a validated hit series Careful interpretation of the output from HTS is a key step towards identifying validated hit series as there are many opportunities for assay interference effects to disguise the true mode of action of com- pounds. While there are a number of generalisa- tions to assist this interpretation in the form of ‘at risk’ structures, new confounding effects continue to be discovered and, in some cases, published (vide supra) demonstrating the subtlety of the interference mechanisms. We believe that being forewarned is being forearmed and that the chance of obtaining genuine validated hit series is greatly enhanced by learning what effects common classes of interference compounds have on an assay prior to running the full screen. Liabilities can be identi- fied, and assay conditions modified to reduce or exclude these liabilities, or appropriate deselection strategies can be put in place to interrogate hits for possessing these liabilities. To this aim we have found the use of a ‘robustness set’ significantly assists in our assay development work and we look for continuous improvement of this set by adding new classes of interference identified in our ongo- ing screening campaigns. Time and effort spent at this stage prior to HTS pays dividends as it helps reduce the chances of costly follow-up of false pos- itives and potentially the more serious loss of false negatives. While these are issues in the earliest stages of inventing a new medicine, the quality of this early work sets the trajectory for success for the whole project and increases the likelihood of new molecules reaching and ultimately bringing benefits to patients.


Acknowledgements The research leading to some of the results described here was funded by a grant provided by the Innovative Medicines


Initiative Joint


Undertaking Grant Agreement 115489. Funding was also provided by the Scottish Universities Life Sciences Alliance.


DDW


Dr Phil Jones is Chief Scientific Officer of BioAscent Discovery. He has more than 30 years’


58 Drug Discovery World Fall 2019


medicinal chemistry and drug discovery experience from Roche, Organon, Schering-Plough, Merck and the University of Dundee including senior roles as Executive Director and Acting Site Head. He was a member of the Research Leadership Council at Schering-Plough. Numerous clinical candidates resulted from groups for which he was responsible. These span a broad range of target families and therapeutic areas.


Dr Stuart McElroy is Director of Biosciences at BioAscent Discovery. With more than 12 years working in drug discovery, Stuart has extensive experience of developing and trouble-shooting novel screening assays, designing screening cas- cades, compound screening, hit validation and sup- porting hit to lead and lead optimisation pro- grammes. Throughout the five years of the European Lead Factory project, he held the posi- tion of Head of Biology at the European Screening Centre (ESC), leading a team of bioscientists in prosecuting and triaging the output of more than 90 high throughput screens across all major target classes and disease indications.


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