Virtual Screening of a Chemically Diverse "Superscaffold" Library Enables Ligand Discovery for a Key GPCR Target.

Saheem Zaidi, Elias Picazo, Julie E Pickett, Shubhangi Aggarwal, Joice Thomas, Christos Illiopoulis-Tsoutsouvas, Evan Carlton Smith, Austen Le, Dmitry Eremin, Valery V Fokin, Sydney Hiller, Anastasiia V Sadybekov, Katharina Grotsch, Alexandros Makriyannis, Cesar Reyes, Yongfeng Liu, Bryan L Roth, Vsevolod Katritch

Journal: ACS chemical biology 2024;19(4):866-874

PMID: 38598723

Free Full Text on PubMed Central View on PubMed

Abstract

The advent of ultra-large libraries of drug-like compounds has significantly broadened the possibilities in structure-based virtual screening, accelerating the discovery and optimization of high-quality lead chemotypes for diverse clinical targets. Compared to traditional high-throughput screening, which is constrained to libraries of approximately one million compounds, the ultra-large virtual screening approach offers substantial advantages in both cost and time efficiency. By expanding the chemical space with compounds synthesized from easily accessible and reproducible reactions and utilizing a large, diverse set of building blocks, we can enhance both the diversity and quality of the discovered lead chemotypes. In this study, we explore new chemical spaces using reactions of sulfur(VI) fluorides to create a combinatorial library consisting of several hundred million compounds. We screened this virtual library for cannabinoid type II receptor (CB) antagonists using the high-resolution structure in conjunction with a rationally designed antagonist, AM10257. The top-predicted compounds were then synthesized and tested in vitro for CB binding and functional antagonism, achieving an experimentally validated hit rate of 55%. Our findings demonstrate the effectiveness of reliable reactions, such as sulfur fluoride exchange, in diversifying ultra-large chemical spaces and facilitate the discovery of new lead compounds for important biological targets.

Address: Department of Chemistry, the Bridge Institute, University of Southern California, Los Angeles 90089, California, United States.; Loker Hydrocarbon Research Institute, University of Southern California, Los Angeles 90089, California, United States.; Department of Quantitative and Computational Biology, University of Southern California, Los Angeles 90089, California, United States.; Department of Chemistry, the Bridge Institute, University of Southern California, Los Angeles 90089, California, United States.; Department of Pharmacology, School of Medicine, University of North Carolina, Chapel Hill 27599, North Carolina, United States.; Psychoactive Drug Screening Program, National Institute of Mental Health, School of Medicine, University of North Carolina, Chapel Hill 27599, North Carolina, United States.; Department of Pharmaceutical Sciences, Center for Drug Discovery, Boston 02115, Massachusetts, United States.; Department of Chemistry and Chemical Biology, Northeastern University, Boston 02115, Massachusetts, United States.; Loker Hydrocarbon Research Institute, University of Southern California, Los Angeles 90089, California, United States.; Department of Pharmacology, School of Medicine, University of North Carolina, Chapel Hill 27599, North Carolina, United States.; Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill 27599, North Carolina, United States.; Psychoactive Drug Screening Program, National Institute of Mental Health, School of Medicine, University of North Carolina, Chapel Hill 27599, North Carolina, United States.; Department of Chemistry, the Bridge Institute, University of Southern California, Los Angeles 90089, California, United States.; Department of Quantitative and Computational Biology, University of Southern California, Los Angeles 90089, California, United States.

DOI: 10.1021/acschembio.3c00602

Link outs

Free resources

Full Text Sources:

https://pmc.ncbi.nlm.nih.gov/articles/pmid/3859872...

Subscription / membership required

Full Text Sources:

https://doi.org/10.1021/acschembio.3c00602

MeSH Terms: High-Throughput Screening Assays, Ligands, Small Molecule Libraries, Receptors, G-Protein-Coupled, Drug Discovery, Receptor, Cannabinoid, CB2