Designing new medicines more cheaply and quickly is tightly linked to the quest of exploring chemical space more widely and efficiently. Chemical space is monumentally large, but recent advances in computer software and hardware have enabled researchers to navigate virtual chemical spaces containing billions of chemical structures. This review specifically concerns collections of many millions or even billions of enumerated chemical structures as well as even larger chemical spaces that are not fully enumerated. We present examples of chemical libraries and spaces and the means used to construct them, and we discuss new technologies for searching huge libraries and for searching combinatorially in chemical space. We also cover space navigation techniques and consider new approaches to de novo drug design and the impact of the "autonomous laboratory" on synthesis of designed compounds. Finally, we summarize some other challenges and opportunities for the future. 

Exploration of Ultralarge Compound Collections for Drug Discovery

Visible Light-Promoted Divergent Benzoheterocyclization from Aldehydes for DNA-Encoded Chemical Libraries.

Photoredox Deaminative Alkylation in DNA-Encoded Library Synthesis.

Inspired by diversity-oriented synthesis, we have developed a series of DNA-compatible transformations utilizing on-DNA vinyl azide as a synthon to forge divergent N-heterocyclic scaffolds. Polysubstituted imidazoles and isoquinolines were efficiently obtained with moderate-to-excellent conversions. Besides, the "one-pot" strategy to prepare in-house on-DNA vinyl azides afforded synthons readily. Results from substrate scope exploration and enzymatic ligation further demonstrate the feasibility of these N-heterocycle syntheses in DNA-encoded chemical library construction.

Vinyl azide as a synthon for DNA-compatible divergent transformations into N-heterocycles.

On-DNA Synthesis of Functionalized 4H-Pyran Scaffolds for Focused DNA-Encoded Chemical Libraries.

High-power screening (HPS) empowered by DNA-encoded libraries

Paul Greengard's name is and will remain profoundly associated with Neuroscience, with brain signaling and chemical transmission, with Parkinson's and Alzheimer's diseases, with fundamental discoveries and solving paradoxes, but much less perhaps with drug discovery. This should not be mistaken as disdain. Paul in fact did contemplate developing therapeutic avenues to actually treat brain diseases much more than it is known, perhaps during his entire career, and certainly over the last two decades. As a matter of fact, he did more than contemplate it, he directly and indirectly contributed in the development of treatments for neurological diseases and disorders. Paul's impact on fundamental aspects of the brain has been so gargantuan that any other aspect of Paul's life will have difficulty to shine. It is precisely this less known aspect of Paul's career that will be covered in this review. We will discover how Paul very early on moved away from biophysics to avoid working on nuclear weapons and instead started his career in the pharmacological spheres of a large pharmaceutical company.

Vijay Kumar Siripuram

Papers

High-power screening (HPS) empowered by DNA-encoded libraries

Paul Greengard: A persistent desire to comprehend the brain, and also to fix it.