An Analysis of Different Components of a High-Throughput Screening Library

Abstract

Since many projects at pharmaceutical organizations get their start from a high-throughput screening (HTS) campaign, improving the quality of the HTS deck can improve the likelihood of discovering a high-quality lead molecule that can be progressed to a drug candidate. Over the past decade, Janssen has implemented several strategies for external compound acquisition to augment the screening deck beyond the chemical space and number of molecules synthesized for internal projects. In this report, we analyzed the performance of each of those compound collections in the screening campaigns performed internally within Janssen during the last five years. We classified the screening library into two broad categories: Internal and External. The comparison of the performance of these sets of libraries was done by considering the primary, confirmation, and dose response hit rates. Our analysis revealed that Internal compounds (resulting from numerous medicinal chemistry efforts against diverse protein targets) have higher average confirmation hit rates than External ones; however, actives from both categories show similar probabilities of hitting multiple distinct targets. We also investigated the property landscape of both sets of libraries to identify the key elements which make a difference in these categories of compounds. From this analysis, Janssen aims to understand the descriptor landscape of the compounds with the highest hit rates and to use them for improving its future acquisition strategies as well as to inform our plating strategy.

Trends in Hit-to-Lead Optimization Following DNA-Encoded Library Screens

“…To add a reference data set, HTS hits are plotted in Figure A as purple open circles. Because public access to HTS hit structures is limited, we enabled this comparison using Janssen HTS data, for a collection of hits published previously …”

“…Because public access to HTS hit structures is limited, we enabled this comparison using Janssen HTS data, for a collection of hits published previously. 17 Figure 2A compares optimizable DEL hits (blue) and leads (red) with the total DEL hit space (gray) and Janssen HTS hit space (purple) across MW and cLogP. The total DEL hit space lies in a MW range which is higher than the HTS hit space (∼400−1100 vs ∼200−700 Da), but the cLogP range is similar.…”

Rigorous Free Energy Simulations in Virtual Screening

“…Still, HTS remains very expensive and time-consuming . Even when HTS is performed, there can be a dearth of hits for challenging targets (e.g., KRAS, MYC, STING, PPIs, and others) because the existing chemical libraries have been built around more traditional targets (e.g., kinases, proteases, and GPCRs − and might not contain any molecules that bind to the target of interest.…”

Evolution of Novartis’ Small Molecule Screening Deck Design

“…Plate-based high throughput screening (HTS) is still a major source of small molecule hits in drug discovery, , despite the emergence of plateless encoded screening approaches, such as DNA-encoded libraries − and microfluidics-based methods, as well as the advancements in computational virtual screening methods . Therefore, many pharmaceutical companies continue to invest in plate-based low molecular weight (LMW) screening decks and consider them key assets. − …”