Catalyzing Confidence: A Novel Strategy for Enhancing DEL Hit Validation in Drug Discovery
May 15, 2024 @ 15:00 – 15:45 CEST
Drug Discovery Seminars: Catalyzing Confidence: A Novel Strategy for Enhancing DEL Hit Validation in Drug Discovery
Presenter: Dr Stefan Geschwindner, PhD, Director Biophysics, AstraZeneca, Mölndal, Sweden
Host: Pauliina Turunen, Unit Target Protein Engineering (TPE), SciLifeLab DDD
Abstract
In the realm of drug discovery, validating hits derived from DNA-encoded library (DEL) screening is an indispensable step. This process necessitates the resynthesis and retesting of compounds to ascertain the consistency of observed activity while mitigating experimental artifacts. However, the complexity arises from the fact that DNA barcodes in DEL libraries encode synthetic routes rather than chemical structures. This intricacy often leads to challenges in identifying genuine actives, primarily due to incomplete chemical transformations during encoding, resulting in low validation rates.
In response, we will present a novel strategy for DEL hit validation. We will elucidate our approach, which prominently features on-DNA compound resynthesis, mirroring the methods employed during initial library synthesis. This seamlessly integrates with subsequent hit validation endeavors by using highly sensitivity surface-based biosensing in combination with a novel assay format. We will illustrate affinity correlations between on-DNA and off-DNA compounds, offer insights into assay development, and emphasize the utilization of enhanced sensitivity to allow us to detect low-abundancy on-DNA compounds. We will describe a systematic framework for DEL hit validation, enhancing the identification of genuine binders with unwavering confidence and heightened sensitivity for drug discovery.
Speakers biography
Dr. Stefan Geschwindner is currently a Director at AstraZeneca R&D Gothenburg in Sweden where he is heading the Biophysics department within Discovery Sciences. He obtained his Ph.D. at the University of Frankfurt/Germany working predominantly with NMR to elucidate protein structures. After his Ph.D. he joined the Astra Structural Chemistry Laboratory with focus on protein engineering and characterization and helped to implement a variety of different biophysical methods and technologies in the early drug discovery process. Before moving into his current role, he had different roles as Team leader in Protein Engineering and as Principal Scientist in Biophysics. His over 50 peer-reviewed publications are frequently cited leading to an h-index of 26.
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