Global Health Chemical Diversity Library

Abbreviations BMGF - Bill & Melinda Gates Foundation Fsp3 - fraction of sp3 carbons GHCDL - Global Health Chemical Diversity Library HBA - hydrogen bond acceptor HBD - hydrogen bond donor Rot_Bonds - rotatable bonds TPSA - topological polar surface area UoD – University of Dundee

Introduction to the GHCDL 68,689 compound library Designed for screening against the BMGF priority pathogens Designed to interact with diverse range of biological targets Commercially sourced compounds from reputable vendors Library available for 25 screens over a 3 year period Lead-like physicochemical properties with enhanced Fsp3 character Filtered to remove unwanted groups Enriched in novel chemotypes* *Novelty defined as compounds dissimilar to compounds already known to have been screened against the Bill & Melinda Gates Foundation priority pathogens

GHCDL physchem profile Mean MW = 320.7 Mean logP = 2.0 Mean HBD = 0.9 Mean HBA = 5.6

GHCDL physchem profile Mean TPSA = 64.2 Mean Rot_Bonds = 4.5 Mean Aromatic_Rings = 1.8 Mean Fsp3 = 0.48

Abbvie physchem tiering GHCDL Tier Mean Tier = 1.58 Bioorg. Med. Chem. 2012, 20, 4564–4573

Structural alerts Library filtered using 3 sets of complementary structural alerts Eli Lilly, PAINS and Dundee alerts Remove chemically reactive/unstable compounds Remove frequent hitters (fluorescent cmpds, redox active, aggregators etc.) Remove known toxicophores Eli Lilly: J. Med. Chem. 2012, 55, 9763−9772 PAINS: J. Med. Chem. 2010, 53, 2719–2740

High quality diverse chemotypes >14,000 clusters Average cluster size 5 compounds Cluster size range 3 - 14 compounds Sourced from 19 vendors including: Analyticon Asclepia Asinex Bionet Chembridge ChemDiv Chemroutes ChemX Edelris Maybridge Enamine Interbioscreen Life Chemicals Princeton Specs Timtec UORSY Vitas WuXi

What to expect Access to 68,689 compound library Assay ready 384 well plates for the primary screen Cherry picking for active confirmation at a single concentration Dose response plate creation of confirmed actives Data analysis using ActivityBaseTM protocols Compound and data management provided by the Drug Discovery Unit (UoD) Electronic file containing structures of library compounds with calculated properties and catalogue codes Virtual libraries to aid hit expansion 4.5M compound drug-like library with properties and catalogue numbers Smaller sets can also be accessed for lower throughput assays 8,890 compound set comprising 3 compounds per cluster (384 well)

How it works Screening centre BMGF & UoD UoD Abbreviation Submit project proposal to UoD/BMGF BMGF & UoD Successful project assessment Complete SOP template & send to UoD UoD Primary screen plates prepared & delivered to screening centre Screening data generated & sent to UoD Data analysed and sent to screening centre along with plate map Hit selection/cherry pick list sent to UoD Single concentration active confirmation plates sent to screening centre Data generated & sent to UoD IC50 pick list sent to UoD Dose response plates sent to screening centre Chembl Data released to Chembl 1 year after final data release to UoD* Abbreviation UoD – University of Dundee *All data received by the UoD will be made Public within 1 years of final data release to Univ. of Dundee. Release of data into the public domain can be delayed in cases were groups are still actively working on a chemical series derived from the library and require more time to secure an adequate intellectual property position. Data release may also be brought forward at the request of the originating screening centre.

FAQ’s Q. Who will assess my application to screen the GHCDL? A. The University of Dundee guided by input from the Bill & Melinda Gates Foundation. Q. Can I change my mind and screen the library against another target/pathogen? A. The GHCDL should only be screened against the previously agreed target/pathogen in the previously agreed format. Q. Why do we need to release our raw data? A. The UoD and BMGF wish to capture high level data on the performance of the library e.g. hit rates, frequent hitter activity etc. The data and assay conditions will also be released into the public domain after 1 year to aid the research community working on diseases of the developing world. Q. Does the data have to be released into the public domain after 1 year? A. Data release can be delayed in cases were groups are still actively working on a chemical series derived from the GHCDL and require more time to secure an adequate intellectual property position. Q. Can we patent compounds in the GHCDL? At the discretion of the project, any derivatives of the GHCDL compounds and any intellectual property residing in those derivatives shall be owned by the party creating them. No party will seek to obtain any other intellectual property rights whatsoever in the GHCDL compounds including, without limitation, any new formulations, uses (medical or otherwise), applications or methods of administration thereof.

FAQ’s cont. Q. Are there any restrictions around publications arising from the screening of the GHCDL? A. No. All publications should acknowledge the University of Dundee Drug Discovery Unit for the design and supply of the GHCDL. The University of Dundee may publish high level data on the performance of the library, no data will be published that would endanger the intellectual property position of any project. All parties will get appropriate acknowledgement in any data release or publication. Q. Who should I contact for further information? A. Professor Paul Wyatt, College of Life Sciences, University of Dundee, Dundee Email: p.g.wyatt@dundee.ac.uk