Beyond protein binding: recent advances in screening DNA-encoded libraries

Abstract

DNA-encoded libraries are usually screened against tagged proteins to identify ligands, but many other screening modalities either have been, or likely will be, developed that expand the utility of these libraries as a source of bioactive molecules.

G protein-coupled receptors: structure- and function-based drug discovery

“…Reduced diversity, less novelty Ensemble docking [235][236][237] Considering protein flexibility, improved enrichment factors, rescue of false-negative ligands Increased computational burden, pose evaluation, false positive Energy-based pose evaluation [248][249][250][251][252] Improved scoring and ranking ability Substantial computational burden, method validation target dependency 159,160,242 It was reported that a PAM of M2R is located above the orthosteric site and interacts with ECLs. Korczynska et al screened 4.6 million molecules against the allosteric sites of M2R and identified a PAM that potentiated the action of antagonist N-methyl scopolamine (NMS).…”

“…Specifically, DEL has emerged as a powerful approach to drug discovery. [248][249][250][251] Created by split and pool synthesis, DEL usually contains hundreds of thousands to billions of distinct small molecule-DNA conjugates. A majority of DEL-based HTS reported to date involve incubation of an immobilized target protein with the library before the protein-ligand complexes are isolated.…”

“…Encoding DNA tags associated with the immobilized target are then amplified and sequenced to assign relevant chemical structures. 250,251 Although DEL was predominantly applied to ligand screening against soluble proteins such as enzymes, successful adaptation of this technique to GPCRs was reported in a few cases. [252][253][254][255] Lefkowitz group reported the discovery of a NAM for β 2 AR by screening a DEL of 190 million.…”

DNA Encoded Libraries: A Visitor's Guide

“…Many relevant pathologies/phenotypes are simply not affected through such interactions, as supported by the large number of DEL hits that ultimately have no activity in vitro or in vivo. [25,40] To this end, activity-based DEL selections that rely on more complex biochemical assays would be a powerful tool. Recently, Paegel and coworkers reported a microfluidics-based system that allows a one-bead-one-compound (OBOC) DEL to be selected for activity instead of merely binding ( Figure 3C).…”

“…Although expanding the proteome available to DEL selections is a valuable task, these protocols are inherently restricted to small molecule‐protein binding. Many relevant pathologies/phenotypes are simply not affected through such interactions, as supported by the large number of DEL hits that ultimately have no activity in vitro or in vivo . To this end, activity‐based DEL selections that rely on more complex biochemical assays would be a powerful tool.…”