Hunting for drugs in chemical space

Hunting for drugs in chemical space

Connecting chemical building blocks allows drug hunters to explore a much bigger chemical space than before. The challenge is to narrow this field of compounds to something manageable. To do that, chemists are turning to new computational tools to navigate this increasingly huge chemical universe, and they are combining technologies. Experts say these new approaches should speed up the identification process, and industry is investing time and money to optimize the hunt.

Back in 1996, a paper came out that has been cited time and time again. In a footnote to a figure caption , Regine S. Bohacek, Colin McMartin, and Wayne C. Guida of Ciba-Geigy estimated that at least 10 63 small, drug-like molecules could be produced through stitching together up to 30 carbon, nitrogen, oxygen, and sulfur atoms in different arrangements ( Med. Res. Rev. 1996 , 16 , 3).

And yet a look at drugs that have made it into the clinic reveals that the pharmaceutical industry has explored only a fraction of that universe—in terms of the number of approved drugs and the chemical diversity these molecules represent. As medicinal chemists tweak compounds along the way to a final drug, small molecular changes can make big differences in activity and toxicity. But as a first step, scientists have to know what direction they want to explore. “In the drug design process, you have to start with something,” says Matthias Rarey of the University of Hamburg. Rarey works in cheminformatics, meaning he describes molecules computationally. He says drug hunters don’t want to waste time and money making the wrong compounds at the very beginning. Sources: Med. Res. Rev. 1996, 16, 3; European Space Agency; Drug Discovery Today 2019, DOI: 10.1016/j.drudis.2019.02.013; DrugBank Online. Many diseases are caused by misfunctioning proteins, and these are what drugs often target, fixing the disease by modifying the protein or how it works. Finding the right molecule to do that is the job of the drug hunters. To start, they need to find a “hit” that they can build on and improve through rounds of experimentation.

One way drug hunters have traditionally looked for a starting point has been high-throughput screening , which relies on arrays of small quantities of compounds, usually stored in organic solvents, that are tested against a target. Pharmaceutical consultant Wendy Warr of Wendy Warr & Associates recalls how in the mid-1990s, chemists were focused just on making or acquiring more and more compounds to feed into these assays.

“And then they began to realize, well, you don’t just make everything,” she says. “You’ve got to use some common sense. You’ve got to design a library of diverse, drug-like compounds.”

But the number of screening compounds available is now growing again and becoming bigger than ever—through both physical and virtual libraries. Companies like Ukraine’s Enamine and OTAVAchemicals and China’s WuXi AppTec offer catalogs of billions of synthetically available compounds. Even larger are the in-house virtual libraries, or spaces, owned by big pharmaceutical firms. Merck KGaA, for example, has the Merck Accessible Inventory (MASSIV), a virtual space of 10 20 molecules. That’s similar in scale to the number of stars in the universe.

These libraries virtually store compounds that the labs can create from building-block molecules they keep on hand. When chemists order these compounds, they aren’t flicking through a catalog but are searching computationally, and the compounds that are returned are created dynamically from the data about the constituent building blocks and the reactions they can undergo. To navigate this growing complexity, researchers have to be smart in their choices: in how they design new compounds, build those compounds, and combine screening methods. They can’t screen everything, so they need to search where they think they’ll have the most success. And that means the importance of computation has increased.

“I think we really see a shift now because of these large, make-on-demand compound catalogs,” Rarey says. The number of possibilities is just too large, he says. “So there is always a computational element in early-phase drug discovery now, and I think this will remain also in the future.”

Enamine, for example, has been supplying screening compounds to drug hunters since the early 1990s. But what started as a library of a few thousand physical compounds that customers could order has now grown to a catalog of 23 billion possibilities. The firm doesn’t have them all on hand, but it has the pieces and expertise available to build what customers request.

Yurii Moroz, of the screening-chemical supplier Chemspace, says that in 2021, Chemspace customers ordered over 200,000 Enamine […]

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