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

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 (CB2) 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 CB2 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.

Between Science and Big Business: Tapping Mary Jane's Uncharted Potential.

At the intersection of science and medicine, government policy, and pop culture, cannabis has prompted society since the beginning of recorded history. And yet, there is comparatively little replicable data on the plant, its constituents, and their capacity to modify human physiology. Over the past decades, several findings have pointed toward the importance of the endogenous cannabinoid system in maintaining homeostasis, making it an important target for various diseases. Here, we summarize the current state of knowledge on endogenous- and plant-based cannabinoids, address the issues related to cannabinoid-based drug discovery, and incite efforts to utilize their polypharmacological profile toward tackling diseases with a complex underlying pathophysiology. By fusing modern science and technology with the empirical data that has been gathered over centuries, we propose an outlook that could help us overcome the dearth of innovation for new drugs and synchronously redefine the future of drug discovery. Simultaneously, we call attention to the startling disconnect between the scientific, regulatory, and corporate entities that is becoming increasingly evident in this booming industry.