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Fragment Based Drug Discovery: Automated Analysis and Reviewing
Patrick Wheeler ACD/Labs, July 2014
NMR Screening
NMR is one of an array of screening possibilities in
the cascade of drug development steps.
http://www.pharmainfo.net/luckypharmacist/blog/fragment-based-drug-design-fbdd-alternative-approach-traditional-lead
NMR Screening
The Problem - Broadly
• An effort to understand ligand binding to biomolecules
• Many approaches are used
• Originally focused on small molecule fragments, designed to build up larger molecules
• Now includes general first-tier screening activity
NMR Screening
The Problem – Specific to NMR The ACD/Labs Solution
• Analysis by HQI*, Line position, Integral regions – Current: integral regions,
detect changes with and without competitor, find fragments that correlate
• Review by stack plots
• Rapid visualization and decision support
*Hit Quality Index
• Flood of data
• Data requires interpretation – Not all just numbers
• Visualization tools are poor
• Calculations are complex
Spectra Visualization
• Stack plot – Fragments on top
– Bound (protein) and Free (protein plus competitor) at bottom
• Tools to zoom in
Metadata
• Measurements of similarity
• Confidence value: Fraction of fragment lines decreased x Fraction of explained lines decreased
• Confidence can be determined to best meet customer needs
Workflow
• Analyze data – Data analysis fully customizable for customer’s data types and best
automation of hit detection
– Data types dealt with so far: Relaxation, Water LOGSY, STD
– Analysis tools: HQI, Line counts, Integral region count
• Open dataset – One batch at a time
– Can display all or subset of data
– Zoom, find regions that indicate binding, find fragments with lines in region
• Mark CSV with “hits”: can be imported into external systems
Analysis kickoff
Configurable
Analysis Running
Review data
Data Review
• Visually check changes between spectra with and without competitor
• Find Fragments with lines in same region
Metadata
• Provides – Ratings of similarity
– Automated hit analysis
– Regions of change
• Legend – Color coded
– Configurable
Mark hits
• Analyst can mark hits (or unmark hits that are selected by automated analysis)
• Selected hits are automatically entered into spreadsheet
CSV Output