Orthogonal Pooled Screening for Synergistic Drug Interactions
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Solution Overview
Problem
Current high throughput screening methods are inefficient in detecting drug synergy in large chemical libraries, as they are laborious and can only test single known drugs against random compounds, limiting the detection of synergistic interactions.
Innovation Solution
The method of ultra-high throughput screening for synergy (uHTSS) uses orthogonal pooled screening (OPS) to identify active pooled mixtures that exhibit synergy by testing all possible pairs of agents, verifying their activity through self-deconvoluting plates and 3-dimensional data triaging, and characterizing synergistic pairs through serial dilutions and online database searches.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If combinatorial-HTS (cHTS) is used to detect synergistic interactions by systematically creating every possible drug pair, then synergistic interactions can be detected with high frequency, but the method becomes too laborious for routine deployment in large chemical libraries
Solution Approach 1:
The patent segments the large chemical library into smaller pools of compounds. Instead of testing all possible pairs from a large library (which would be prohibitively laborious), the library is divided into multiple pools, and systematic pairing is performed within each pool. This segmentation reduces the computational and experimental burden while maintaining the ability to detect synergistic interactions through the pooled screening approach.
Solution Approach 2:
The patent merges multiple pools of compounds into combination pools for simultaneous screening. By combining pools in a systematic manner and using automated imaging to detect synergistic responses, the method achieves high-throughput screening capability. The merging of pools allows parallel testing of multiple compound combinations, dramatically increasing productivity compared to testing individual pairs sequentially.
2Quantity of substance
If a large chemical library is screened for synergistic interactions using systematic pairing, then comprehensive drug combination data can be obtained, but the labor intensity becomes prohibitive
Solution Approach 1:
The patent employs automated imaging systems and computational algorithms that perform self-service functions. The automated imaging system captures data from pooled screens, and computational methods automatically analyze the images to identify synergistic interactions. This automation eliminates the need for manual intervention in data collection and analysis, reducing labor intensity while enabling comprehensive screening of large numbers of compound pairs.
Solution Approach 2:
The patent replaces manual mechanical operations with automated imaging and computational systems. Instead of researchers manually preparing and analyzing each drug pair, automated liquid handling systems prepare pooled combinations, and imaging systems automatically capture and analyze the results. This substitution of mechanical and manual processes with automated systems dramatically reduces labor intensity while increasing the quantity of compound pairs that can be tested.
3Measurement precision
If known drugs are laboriously paired and tested as binary pools to detect synergistic pairings, then synergistic actions in known drugs can be detected, but the method cannot be used practically for large libraries of diverse compounds
Solution Approach 1:
The patent creates a universal screening platform that can handle both known drugs and large libraries of diverse compounds using the same methodology. The pooled screening approach combined with automated imaging and computational analysis provides a multi-functional system that maintains measurement precision for detecting synergistic pairings while scaling to accommodate large libraries. This universal method eliminates the need for separate approaches for different library sizes or compound types.
Data Source
AI summary
Synergy occurs when combined agents induce a response greater than the sum of their individual effects. The present invention provides new high throughput screening methods to detect agents acting synergistically in orthogonally pooled mixtures. Computational de-convolution of the pooled data with software reveals single-actives in the pools with twice the statistical power and with much greater efficiency than common high throughput screening approaches. Cross-correlating the orthogonal data reveals pools with activity that cannot be ascribed to any single compound. The components of such ‘Orphan’ activity pools are then tested individually and in all possible combination-pairs to identify and confirm synergy. The high throughput screening invention disclosed, which we name “Ultra-High Throughput Screening for Synergy (uHTSS)”, is applicable for more efficiently discovering nucleic acids, proteins and small molecules that act synergistically without having to systematically test each possible pair, as is required by known screening practices.