hot topics in chemoinformatics in the pharmaceutical industry david j. wild, ph.d. scientific...
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Hot Topics in Chemoinformaticsin the Pharmaceutical Industry
David J. Wild, Ph.D.
Scientific Computing Consultant, andAdjunct Professor of Pharmaceutical Engineering at the
University of Michigan
B.Sc Computer SciencePh.D. Chemoinformatics (Willett Lab)
Worked for 5 years in Scientific Computing leadership at Pfizer, responsible for the development of computational tools for scientists
Now run a consulting firm based in Ann Arbor, Mich., and am also an Adjunct Professor at the University of Michigan.
About me
doing some research
Wild Ideas Consultingwww.WildIdeasConsulting.com
University of Michiganwww-personal.engin.umich.edu/~wildd
What we’ll cover today
• Overview of early-stage drug discovery and the big industry concerns
• Using information and technology together to improve the chances of finding a new drug
• Example – High Throughput Screening• Some other examples of “hot” areas
– Genomics & Proteomics Information Handling– Virtual Screening– Combinatorial Chemistry– Design of scientific software
Characteristics of the pharmaceutical industry
• Very segmented market – largest company (Pfizer) only has an 11% market share
• High risk, long term – takes 10-20 years to develop a drug, and most drugs fail to get to market
• Highly regulated (by FDA)• High profit margins for drugs which do make it• Investors traditionally expect high return on
investment• Four main phases: discovery, development,
clinical trials and marketing
R&D spending up, new drugs down
Taken from http://www.newscientistjobs.com/biotech/ernstyoung/blues.jsp
Drug Discovery & Development
Identify disease
Isolate proteininvolved in disease (2-5 years)
Find a drug effectiveagainst disease protein(2-5 years)
Preclinical testing(1-3 years)
Formulation &Scale-up
Human clinical trials(2-10 years)
FDA approval(2-3 years)
File
IN
D
File
NDA
Impact of new technology on drug discovery
• The last few years have seen a number of “revolutionary” new technologies:– Gene chips, genomics and HGP– Bioinformatics & Molecular biology– More protein structures– High-throughput screening & assays– Virtual screening and library design– Docking– Combinatorial chemistry– In-vitro ADME testing– Other computational methods
• How do we make it all work for us?
Identify disease
Isolate protein
Find drug
Preclinical testing
GENOMICS, PROTEOMICS & BIOPHARM.
HIGH THROUGHPUT SCREENING
MOLECULAR MODELING
VIRTUAL SCREENING
COMBINATORIAL CHEMISTRY
IN VITRO & IN SILICO ADME MODELS
Potentially producing many more targetsand “personalized” targets
Screening up to 100,000 compounds aday for activity against a target protein
Using a computer topredict activity
Rapidly producing vast numbersof compounds
Computer graphics & models help improve activity
Tissue and computer models begin to replace animal testing
There is little “hard data” on using the new technologies
• In a sense, the drug design process is becoming a big experiment
• Do we continue as before, and carefully introduce new technologies as we deem appropriate, or do we radically change the way things are done?
• Lots of pressure for the new technologies to yield results quickly
• How do we measure the results?
Some questions being asked
• Is our increasing spending on R&D and new technologies really going to pay off? Or was it a red herring?
• Is the paucity of drugs in the pipeline because we’re not doing things right, or are we just hitting limits on the number of major diseases with potential treatments still to be found? (“all the low-hanging fruit has gone”)
• Should we be looking in new areas (e.g. “life enhancment” rather than “life saving” or “quality of life”)
What’s being done
• Trying to get the right Attrition (=drugs dropping out of the pipeline). Aim to increase early-stage attrition and reduce late-stage attrition
• Risk analysis – look ideally for low-risk, high-payoff drugs
• Using metrics to monitor successes and failures
Analyzing risk
High riskLow payoff
High riskHigh payoff
Low riskLow payoff
Low riskHigh payoff
Using metrics to monitor improvement
• Split the discovery process into discrete units, with key decisions at the end of each unit.
• Come up with measurable properties that can be used to gauge success
• Look for good and bad decisions and why they were made
Stage Decision Point
Target exploration
Go with this target?
HTS Was the screen successful?
HTS Analysis Follow up these 5-10 series
Series Followup
Produce 2-3 lead compounds
ADME study Are compounds safe?
Summary
• The pharmaceutical industry is a high-risk industry with very long development times and short product lifespans
• There has been a lot of investment in new technologies for early stage drug discovery, but so far these are not resulting in more drug candidates (or profits)
• Companies are looking at ways to address this problem including managing attrition, risk analysis and metrics.
How Chemoinformatics can help out
• Producing and manage information for metrics• In-silico analysis to reduce risk, e.g.
– Virtual screening– Library design,– Docking– Cost/benefit analyses
• Making information available at the right time and the right place
• Needs to be integrated into processes
An example: High-Throughput Screening
Screening perhaps millions of compounds in a corporate collection to see if any show activity against a certain disease protein
High-Throughput Screening
• Drug companies now have millions of samples of chemical compounds
• High-throughput screening can test 100,000 compounds a day for activity against a protein target
• Maybe tens of thousands of these compounds will show some activity for the protein
• The chemist needs to intelligently select the 2 - 3 classes of compounds that show the most promise for being drugs to follow-up
Informatics Implications
• Need to be able to store chemical structure and biological data for millions of datapoints– Computational representation of 2D structure
• Need to be able to organize thousands of active compounds into meaningful groups– Use cluster analysis or machine learning methods to group
similar structures together and relate to activity
• Need to learn as much information as possible from the data (data mining)– Apply statistical methods to the structures and related
information
HTS Tools – Tripos SAR Navigator
SAR Navigator is © Tripos, inc., www.tripos.com
BioReason ClassPharmer
• Clusters actives into groups representing series• Attempts to find a scaffold using MCS algorithm• Recovers inactives back into series• Presents series as rows in a “spreadsheet” view• Gives other statistics on series, such as activity
distribution• http://www.bioreason.com
BioReason Classpharmer
www.bioreason.com
BioReason Classpharmer
www.bioreason.com
Strategy for “HTS Triage”
• Run HTS• Decided which compounds are “active” and
which are “inactive”• Cluster the actives to put them into series• Visualize clusters of actives (showing 2D
structures) and pick series of interest• Identify “scaffold” for each series• Use similarity or substructure search on
inactives to find inactives related to these series• Use SAR techniques to discover differences
between actives and inactives in a series
Information generated at different points in the Drug Design process
File
IN
D
File
NDA
Gene chip experiments
Project selection decisionsAssay protocols
HTS resultsSeries selection decisionsSAR studies
Protein structures
Combinatorial Expts.PharmacophoresADME studies
Toxicology studiesScaleup reactions
Lead cmpd decisions
Clinical Trials data
Doctor/patient studies
Marketing, surveys, etc
Information generated at different sites
Distributed goals model
Shared goals model
Information storage breakdowns
• Large amounts of information generated:– Some is not kept at all– Some is kept but loses its meaning
• Often data is kept, but not semantics or decisions– e.g. keep “the HVX2 assay result for this compound was
3.2”, but not what the assay protocol was, whether the compound was considered ‘active’, nor whether it was followed up on.
• “Bigger picture” or derivative information is usually not stored– E.g. “all the compounds with a tri-methyl group seemed
to have much lower activity for this project”
Information access breakdowns
• Some information is only available in one physical location
• Some information is only available within one part of the discovery process
• Often information is not “contextualized” for use outside a particular domain
• When someone is clear about a piece of information they need; that piece of information exists, but they don’t know how to access it.– E.g. What system to use, what Oracle table it’s in, or
even the knowledge of whether that piece of information does exist!
“Missed opportunities”
• Not a specific breakdown, but if the right piece of information had been available at the right time, better decisions could have been made
• E.g.– A group of compounds is being followed up as potential
drugs, but a rival company just applied for a patent on the compounds
– A large amount of money is being spent developing an HTS assay for a target, but marketing research shows any drug is unlikely to be a success
– A group of compounds is selected from an HTS as good candidates for follow up, but 20 years ago they were followed up for a similar project and had severe solubility problems
Information use breakdowns
• The meaning of data is incorrectly interpreted• A single piece of information is used, whilst using
a wider range of information would lead to different conclusions
• Lessons learned from one project are incorrectly applied to another
• “Fuzzy” information is taken as concrete information
What do we do?
• No large company has really solved the problem• But ongoing attempts include:
– Defining information produced and needed at each stage of the discovery process
– Improving processes to be more consistent, especially across different sites
– Improving information flow between departments and sites– Harmonizing terminology across disciplines and sites– Defining needed “management information” as well as raw
data– Looking for “quick win” opportunities
• This will presumably impact what is stored in databases and what software is used– Oracle Chemistry Cartridges help
Some Other Examples
Genomics & Proteomics Information Handling
Virtual ScreeningCombinatorial Chemistry
Design of scientific software
Genomics & Proteomics Information Handling
Understanding the link between diseases, genetic makeup and expression of proteins
Genomics
• Genomics is fast-forwarding our understanding of how DNA, genes, proteins and protein function are related, in both normal and disease conditions
• Human genome project has mapped the genes in human DNA• Hope is that this understanding will provide many more potential
protein targets• Allows potential “personalization” of therapies
ATACGGATTATGCCTA functions
Gene Chips
• “Gene chips” allow us to look for changes in protein expression for different people with a variety of conditions, and to see if the presence of drugs changes that expression
• Makes possible the design of drugs to target different phenotypes
compounds administered
people / conditions
e.g. obese, cancer, caucasian
expression profile
(screen for 35,000 genes)
“Chemogenomics” from Vertex
Video: http://www.vrtx.com/Chemogenonone.html
Virtual Screening
• Build a computational model of activity for a particular target
• Use model to score compounds from “virtual” or real libraries
• Use scores to decide which to make, or pass through a real screen
Computational Models of Activity
• Machine Learning Methods– E.g. Neural nets, Bayesian nets, SVMs, Kahonen nets– Train with compounds of known activity– Predict activity of “unknown” compounds
• Scoring methods– Profile compounds based on properties related to target
• Fast Docking– Rapidly “dock” 3D representations of molecules into 3D
representations of proteins, and score according to how well they bind
Present molecules to model
• We may want to virtual screen– All of a company’s in-house compounds, to see which to
screen first– A compound collection that could be purchased– A potential combinatorial chemistry library, to see if it is
worth making, and if so which to make
• Model will come out with with either prediction of how well each molecule will bind, or a score for each molecule
Combinatorial Chemistry
• By combining molecular “building blocks”, we can create very large numbers of different molecules very quickly.
• Usually involves a “scaffold” molecule, and sets of compounds which can be reacted with the scaffold to place different structures on “attachment points”.
Example Combinatorial Library
NH
R1
R2R3
Scaffold “R”-groups
R1 = OH OCH3
NH2
Cl COOH
R2 = phenyl OH NH2
Br F CN
R3 = CF3
NO2
OCH3
OH phenoxy
Examples
NH
OH
CN
OH
NH
OH
OCH3
NH
C
OH
OHO
CF3
NH
C
OH
OHO
O
For this small library, the numberof possible compounds is
5 x 6 x 5 = 150
Combinatorial Chemistry Issues
• Which R-groups to choose
• Which libraries to make– “Fill out” existing compound collection?– Targeted to a particular protein?– As many compounds as possible?
• Computational profiling of libraries can help– “Virtual libraries” can be assessed on computer
Design of Scientific Software
Problems with scientific software tend to occur because of deficiencies in one of three areas:
Software RelevanceSoftware Usability
Software Management
Software Relevance
• To be able to make software relevant requires the software designer to understand:
– the science, i.e. the domain– the scientific computing techniques that are used in the
domain– the possibilites and limitations of software development.
• Even with this, it’s hard to match the things we can do with the things that people want or need to do
• Techniques like personas and contextual inquiry simply help us understand the people who use the software, their goals, and tasks they want to do
Software relevance:Bridge between computation & science
clusteringsim. searchingactivity modelsscaffold detectiondockinglogp calculation
tasks:
“doing a cluster analysis”
“identifying activity-related fragments”
tools
chemoinformatics science
tasks:
work out a chemical synthesis
choose good reagents
try and document some reactions
goals:
e.g. produce compounds that have high biological activity
?
Software Usability
• Tend to focus on the method and the science, but not how easy it is for people to get their job done using the software
• Programmers tend to make software intuitive for them, but not necessarily the people it is designed for
• A usability lab and other techniques can make a HUGE difference to the satisfaction of users and programmers alike!
Software Management
• Disparate set of tools & platforms • Disparate programming styles, languages• A variety of people tend to be writing software
– Trained software developers– Enthusiastic scientists– Scientific computing specialists
• Focus on the science tends to mean software management is neglected
• Everyone hates traditional software management “rules”• But there are ways of making everything work better and
having more fun doing it!• Have a recommended basic setup that should help a lot
Foundation reading
• “The Inmates Are Running the Asylum” by Alan Cooper
• “Contextual Design” by Hugh Beyer and Karen Holtzblatt
• “Usability Engineering” by Jakob Nielsen• “The Visual Display of Quantitative Information”
by Edward Tufte• “Don’t Make Me Think!” by Steve Krug
• See also, www.WildIdeasConsulting.com
Summary
• R&D in the pharmaceutical industry is undergoing a lot of technological changes, and there is pressure to make the investment pay off
• There is a big need to sensibly use the large amounts of chemical and biological-related information produced in the process
• Thoughtful use of chemoinformatics methods and software is becoming crucial to the success of drug discovery