Vast fields of biologically active chemical space

Exactly 17 years ago, I highlighted a paper from Brian Shoichet’s lab in which he hypothesized that only tiny regions of chemical space are biologically relevant. If so, Practical Fragments quoted, “a major reason why the screening of synthetic compounds ever finds notable hits is that our libraries are biased toward the sort of molecules that proteins have evolved to recognize.” The best scientists continually question their assumptions, and this is exactly what Brian, Bryan Roth, and collaborators at University of California San Francisco and University of North Carolina at Chapel Hill have done in a new open-access J. Med. Chem. paper.

 

The idea that molecules more closely resembling metabolites and natural products would be more likely to be biologically active is reasonable given the promiscuity of many naturally occurring molecules. As the researchers point out, dopamine signals through 5 receptors, while serotonin binds to 14. Nature is the ultimate recycler, constantly reusing chemical motifs.

 

But since 2009 there has been a massive growth of make-on-demand libraries, and these have increasingly diverged from known molecules. Brian has been among the most prolific explorers of this new chemical space, and as he noted in his keynote at DDC 2026, these gargantuan libraries are yielding more hits against more targets.

 

Are these hits more selective? In other words, are molecules that are less “bio-like” likely to bind to fewer targets? This is the question the new paper addresses, focusing on the 5-HT_2A serotonin receptor (5-HT_2AR), the target for a variety of drugs including psychedelics. The researchers have extensively studied this GPCR; we wrote about a successful computational screen here. In the new paper, the researchers compared hits from a previous “make-on-demand” (MoD) library screen of 1.6 billion molecules with a new screen of 3.5 million “in-stock” molecules. As predicted, the in-stock compounds were much more bio-like than the MoD compounds as assessed by several metrics (Tanimoto similarity, Avalon fingerprints, and RDK7 fingerprints, for the cheminformatics aficionados among you).

 

Both libraries were computationally screened using DOCK3.8 against 5-HT_2AR. Of the top scoring hits, 85 molecules from the in-stock library and 384 molecules from the MoD library were tested in a radio-ligand displacement assay. Hit rates were nearly identical at around 24% each. Functional assays revealed the hits to be active, with some acting as agonists while others were antagonists.

 

When tested against related GPCRs, specifically 5-HT_2BR and 5-HT_2CR, the in-stock molecules were more promiscuous than the MoD molecules. But when tested against a panel of 318 GPCRs there were no differences: the in-stock molecules bound on average 1.7% of the receptors while the MoD molecules bound on average 2.1%. The similar promiscuity persisted even when focusing on the 55 aminergic GPCRs (5-HT_2AR is an aminergic GPCR). In fact, the most promiscuous compound of all came from the MoD set and is distinctly not bio-like.

 

Of course, this is just one study, but I suspect it will generalize. In 2009 I questioned whether biologically relevant chemical space is really so sparse. As I wrote then, “consider a vast field of some crop that can only be harvested by night. There are lights scattered haphazardly throughout the field. One might expect that the crops immediately under the lamp posts would be harvested more intensively than crops in darker parts of the field, even if other areas are equally productive. In this scenario, the lamp posts reveal natural products and similar molecules, but much – or even most – of (unlit) chemical space may also be biologically active, it just hasn’t been sampled yet.”

 

There is grandeur in this view of chemical space, which is supported by the new paper. Imagine yourself in the midst of the field on a moonless night. Turn on your headlamp and step forward in any direction. Drug leads glimmer as far as your light can reach.