Chemical space: the final frontier

As the famous first words of Star Trek suggest, space is often considered the “final frontier” — a vast region beyond our tiny world that is largely unknown and yet to be explored. But for some Broad scientists, that distinction goes to a decidedly different area: chemical space.

In this month’s issue of the journal Nature Chemical Biology, the Broad’s Siva Dandapani and Lisa Marcaurelle put forth their vision for how this scientific unknown should be surveyed. Their essay, part of a special anniversary celebration of the journal and the field it chronicles, was selected as one of ten “grand challenge” commentaries, which, the journal’s editors write, “outline the myriad ways that chemical biologists will advance scientific frontiers” in the decades to come.

Chemical space is, simply put, the complete set of all possible chemicals. Imagine Tinkertoys cobbled together in every potential three-dimensional combination. It’s a simplified analogy, for sure, but the idea is valid.

Now, not all of these mythical molecules will be important when it comes to human biology and medicine. Rough estimates of the number of chemicals (or “compounds”) that could operate in humans — that is, chemicals with the capacity to act as drugs — is somewhere on the order of 10⁶⁰ to 10²⁰⁰ different molecules. “So far, chemists have collectively synthesized less than 50 million compounds — just 5 times 10⁷ — over more than a century of research,” Siva, a group leader in medicinal chemistry at the Broad, told me. “Clearly, what we have accomplished [as a field] is absolutely small compared to what is possible.”

The ability to discover drugs with new and interesting capabilities hinges on closing this yawning gap. That is because researchers tend to sift through, or screen, collections of already existing chemicals in order to identify ones with remarkable properties — say, a chemical that can halt a tumor’s spread or alleviate the effects of psychiatric disease.

Yet, as Siva and Lisa explain in their essay, most of the chemical collections that exist today survey the same corner of chemical space, like Tinkertoys put together in slightly different, though largely similar ways. Such undersampling is believed to underlie some of the recent difficulties in identifying drugs that work against certain types of biological molecules (called “targets”) within the human body, leading some scientists to believe that these targets are simply undruggable — or, impossible to block with a drug.

The challenge, then, is to build and amass collections of chemicals that are sufficiently diverse to support a seemingly infinite range of biomedical discoveries. As they write in their essay, Lisa and Siva, together with their colleagues here at the Broad Institute and beyond, are tackling the problem from a couple directions. First, they are creating their own chemicals from scratch, piecing together the “spools” and “sticks” in various different ways, and taking great pains to ensure the end products are sufficiently diverse in structure and different from what is currently available from other sources. “Over the last three years, [we] have produced about 100,000 of these small molecules. These are now actively being screened in various assays at the Broad Institute,” explains Siva.

They are also collaborating with the academic chemists, who can contribute the fruits of their labor — chemical compounds they have constructed in their own laboratories — for study here at the Broad. These compounds often have elaborate chemical structures, often taking years to create, and represent a key untapped resource in the world of drug discovery. As Lisa, director of synthetic chemistry here at the Broad, told me, “We currently have more than 5,000 compounds in our collection that have originated from academic contributors outside of the Broad.”

Finally, it is clear that the path forward requires strong partnerships among researchers in various branches of the natural sciences. As Siva and Lisa urge in their essay, “Synthetic chemists, biologists and screening centers should share information and foster collaborations toward the goal of expanding the druggable chemical space. The next generation of drug discovery relies on it.”

You can read more from Siva and Lisa’s article here (subscription required).

And you can read about another “grand challenge,” written by Broadie Bridget Wagner, here.