Make better drug discovery decisions through collaborative analytics cdd webinar slides
- 1. Make Better Drug Discovery Decisions through Collaborative Analytics Wednesday, March 29, 2017
- 2. Copyright © 2016 All Rights Reserved Collaborative Drug Discovery Kellan Gregory Director of Product Excellence, CDD Moderators Frank Cole US Head of Sales, EAST CDD
- 3. Copyright © 2016 All Rights Reserved Collaborative Drug Discovery Dr. Chris Cooper Sr. Director of Chemistry, TB Alliance, New York, NY Panelists Dr. Matthew Segall CEO Optibrium Ltd Cambridge, UK
- 4. • TB is the leading infectious disease killer, and a top 10 killer worldwide. • TB kills 1 person nearly every 18 seconds; 1.8 million die each year. • 10.4 million new cases annually. • Leading killer of people with AIDS. • Drug resistance is on the rise— 580,000 annual cases. • 1 million children become ill with TB each year and 210,000 die. TB Pandemic Chris Cooper
- 5. Current TB Therapy LONG TB treatment today takes 6-30 months. OLD Arsenal of drugs developed mostly in 1960s. COMPLEX Many pills must be taken daily; drug-resistant treatment includes daily injections. EXPENSIVE Drug-resistant (DR) TB drugs can cost >$10,000 per treatment. INADEQUATE Breeds resistance & default; incompatible with some HIV treatments; DR-TB treatment often fails. One day of treatment for drug-resistant TB 5
- 6. 6 Catalyzing and advancing new TB cures TB Alliance: A Product Development Partnership (PDP) 6 Not for profit organization founded in 2000, with offices in New York, USA; and Pretoria, South Africa (total staff: 48) Developing new TB drugs—and redefining the way TB drugs are developed Virtual business model promotes innovation and efficient, rapid progress Leverage global pipeline of drugs to find the most promising TB regimens Transform TB treatment with new regimens that treat drug-sensitive and drug-resistant TB Ensure beneficial new TB regimens are quickly and widely adopted Largest TB drug pipeline in history
- 7. 7 Achieving maximum impact will require: • Short, simple regimens that are adopted, available and affordable. • Ideally, a universal regimen consisting of all novel drugs that is effective in all people with active TB. • All TB treatments are appropriately formulated for children. Discover, develop and deliver better and faster TB regimens Our Vision: Better TB Medicines for All 7
- 8. Success will require novel drug combinations Product Development Strategy Current Treatment 6-30 Months New Treatments in Development 3-6 Months Aspirational Goal 7-10 Days 8
- 11. 11 Leveraging the best science from around the world A Global Network of Partners
- 12. 12 In Vitro ADME/Tox Testing (CRO #4) • Solubility (clogD), plasma protein binding, %F. • Metabolic stability, CYP450, hERG, Cytotoxicity liabilities, etc. Mouse PO PK (CRO #4). Analogue Synthesis (CRO #1) SAR/SLR In Vitro Testing (Research Institute #3) • Whole Cell Activity – Replicating and non-replicating In Vivo PoC (Chronic Efficacy in Mice) (Research Institute #6) In Vivo PoC (Acute Efficacy in Mice) (Research Institute #5) In Vitro Testing (University #2) • Activity against isolated enzyme • MoA, MoR “Typical” TB Alliance Lead Optimization Project Multiple data sources Lab-to-lab variability, as well as site-to-site Multiple data types Assimilate, integrate and analyze relevant data Improve decision-making
- 13. Copyright © 2017 All Rights Reserved Collaborative Drug Discovery CDD Vault Full Solution
- 14. Copyright © 2017 All Rights Reserved Collaborative Drug Discovery CDD Vault -- Advantage
- 15. Whole Solution: Biology Assay Data , QC, & SAR
- 17. Copyright © 2016 All Rights Reserved Collaborative Drug Discovery Beautiful Data Visualization
- 18. © 2017 Optibrium Ltd. US Patent Numbers 9,224,098 and 9,367,812 Optibrium™, StarDrop™, Card View™, Nova™, Auto-Modeller™, Glowing Molecule™ and MPO Explorer™ are trademarks of Optibrium Ltd. Multi-parameter Optimisation in Drug Discovery Targeting compounds with a high chance of success Matt Segall, CEO Optibrium Ltd. – matt@optibrium.com 18
- 19. © 2017 Optibrium Ltd. 19 The Objectives of Drug Discovery Multi-parameter optimisation • Identify chemistries with an optimal balance of properties • Quickly identify situations when such a balance is not possible −Fail fast, fail cheap −Only when confident −Avoid missed opportunities Absorption Metabolic stability Potency Safety Property 1 Property2 X Solubility Absorption Solubility Metabolic stability Potency Safety Property2 Property 1 Drug X Hit No good drug M.D. Segall (2012) Curr. Pharm. Des. 18(9) pp. 1292-1310
- 20. © 2017 Optibrium Ltd. Challenge 1: Data overload Visualisation is important but not enough… 20 How can you make a confident decision by looking at these? *Segall and Champness (2010) GEN, 30 (Sep 1) http://bit.ly/cSx4Tm
- 21. © 2017 Optibrium Ltd. Challenge 2: Uncertainty in Data • Experimental variability/error − Single measurements: assay variability o pKi/pIC50 ~ 0.3 – 0.7 log units (factor of 2-5 in Ki/IC50) − Multiple replicates: mean and standard error in mean • Statistical uncertainty in predictions − Standard error of prediction o logP ~ 0.4 -0.5 log units o logS ~ 0.7 – 0.8 log units o pKi ~ 0.9 – 1.0 log units − Need to consider domain of applicability 21 RMSE=0.8 log units Segall and Champness (2015) J. Comput.-Aided Mol. Des. 29(9) p. 809 0 0.1 0.2 0.3 0.4 0.5 0.6 5 7 9 11 13 15 Probability Solubility
- 22. © 2017 Optibrium Ltd. Probabilistic Scoring Integrated assessment of data against project criteria Uniquely accounts for the uncertainties in all compound- related data (experimental or calculated) User-defined scoring profile Compounds ranked by likelihood of success M.D. Segall (2012) Curr. Pharm. Des. 18(9) pp. 1292-1310
- 23. © 2017 Optibrium Ltd. Probabilistic Scoring User-defined scoring profile Compounds ranked by likelihood of success Histograms for quick visual guide to compound properties M.D. Segall (2012) Curr. Pharm. Des. 18(9) pp. 1292-1310 Integrated assessment of data against project criteria Uniquely accounts for the uncertainties in all compound- related data (experimental or calculated)
- 24. StarDrop™
- 25. © 2017 Optibrium Ltd. StarDrop – Core Features Guiding decisions from selection to design… • Probabilistic Scoring − Define your property profile and quickly target high quality compounds • Chemical space and selection − Balance quality and diversity to avoid missed opportunities • Card View™, data visualisation and SAR analysis − Understand the structure-activity relationships in your chemical series • Interactive design and Glowing Molecule™ − Guide the design of balanced compounds 25
- 26. © 2017 Optibrium Ltd. StarDrop Plug-in Modules Extend Core Capabilities torch3D™ is a trademark of Cresset BioMolecular Discovery Ltd. BIOSTER™ is a trademark of Digital Chemistry Ltd. Derek Nexus™ is a trademark of Lhasa Limited. SeeSAR™ is a trademark for BioSolveIT GmbH. ADME QSAR Auto Modeller™ P450 High quality predictive models of key ADME properties Build and validate robust models tailored to your chemistry QM simulations identify sites of metabolism and lability for P450s Derek Nexus™ Nova™ BIOSTER™ Knowledge-based prediction of >40 toxicity endpoints Generate and prioritise new, relevant compound ideas Explore >25k transformations with the Nova module torch3D™ SeeSAR™ MPO Explorer™ Apply 3D SAR to identify and optimise novel actives Visualise protein-ligand interactions in 3D Develop multi-parameter optimisation strategies
- 27. © 2017 Optibrium Ltd. Conclusion A complete platform for data visualisation, analysis and compound design • Website: www.optibrium.com/stardrop − Detailed information − Case studies • Online community: www.optibrium.com/community − Publications, presentations and posters − Demo videos, tutorials and hints and tips − Download free add-ons for StarDrop including CDD Vault plug-in • Email: − matt@optibrium.com 27
- 28. In Vitro ADME/Tox Testing (CRO #4) • Solubility (clogD), plasma protein binding, %F. • Metabolic stability, CYP450, hERG, Cytotoxicity liabilities, etc. Mouse PO PK (CRO #4). Analogue Synthesis (CRO #1) SAR/SLR In Vitro Testing (Research Institute #3) • Whole Cell Activity – Replicating and non-replicating In Vivo PoC (Chronic Efficacy in Mice) (Research Institute #6) In Vivo PoC (Acute Efficacy in Mice) (Research Institute #6) In Vitro Testing (University #2) • Activity against isolated enzyme • MoA, MoR “Typical” TB Alliance Lead Optimization Project Multiple data sources Lab-to-lab variability, as well as site-to-site Multiple data types Assimilate, integrate and analyze relevant data Improve decision-making Chris Cooper
- 29. Integration of CDD • Available to all TB Alliance research partners (CRO’s, universities, research institutes) to facilitate direct data upload. • CDD Vault integrated across TB Drug Accelerator (TBDA) consortium -> enhanced project coordination for global TB network. • Initial raw data can be uploaded to private “sandbox” -> permits data QC prior to publication.
- 30. Integration of CDD • Single data source for: – Compound batch registration – Chemical structures, descriptors – In vitro biochemical data – In vivo pharmacokinetic data – In vivo efficacy data – Tox. data, etc. – Biological/pharmacological protocols • CDD Visualization-> Provides simple graphical interface view of data parameters/trends.
- 31. In Vitro ADME/Tox Testing (CRO #4) • Solubility (clogD), plasma protein binding, %F. • Metabolic stability, CYP450, hERG, Cytotoxicity liabilities, etc. Mouse PO PK (CRO #4). Analogue Synthesis (CRO #1) SAR/SLR In Vitro Testing (Research Institute #3) • Whole Cell Activity – Replicating and non-replicating In Vivo PoC (Chronic Efficacy in Mice) (Research Institute #6) In Vivo PoC (Acute Efficacy in Mice) (Research Institute #6) In Vitro Testing (University #2) • Activity against isolated enzyme • MoA, MoR “Typical” TB Alliance Lead Optimization Project Multiple data sources Lab-to-lab variability, as well as site-to-site Multiple data types Assimilate, integrate and analyze relevant data Improve decision-making
- 32. Integration of Optibrium (StarDrop) • Provides intuitive graphical depictions of important SAR/SLR trends (physicochemical, potency/efficacy, toxicities, etc.).
- 33. Integration of Optibrium (StarDrop) !!!!!! • Multidimensional chemistry space models -> provide guidance for new analogue design and synthesis. Integration of CDD + StarDrop has improved the quality and speed of med. chem. decision-making across TB Alliance discovery portfolio
- 34. Copyright © 2016 All Rights Reserved Collaborative Drug Discovery Q&A
- 35. Copyright © 2016 All Rights Reserved Collaborative Drug Discovery Dr. Chris Cooper Sr. Director of Chemistry, TB Alliance, New York, NY Christopher.cooper@tballiance.org Thank You Panelists Dr. Matthew Segall CEO Optibrium Ltd Cambridge, UK matt@optibrium.com
- 36. Copyright © 2016 All Rights Reserved Collaborative Drug Discovery Thank you all for your participation Visit our website or contact us at info@collaborativedrug.com