DOS library a hit against neglected diseases
At the recent Applied Pharmaceutical Chemistry meeting in Boston Ben Munoz, director of Medicinal Chemistry within the Broad’s Chemical Biology Platform, spoke about the exciting work he and others at the Broad have been doing for the past year screening the Broad’s unique small molecule library against targets in infectious and neglected diseases, like malaria and Chagas disease.
Ben’s team has just started down the road of screening the Broad’s expansive set of molecules for possible hits, or lead compounds that show activity against the disease under study. These compounds were developed by the Broad’s diversity-oriented synthesis (DOS) group, which is led by Jeremy Duvall.
The DOS compounds are a totally unique collection that allows Broad researchers to investigate chemical compounds that are traditionally not represented in pharmaceutical libraries. “We screen something very unique that hasn’t been screened anywhere and we’re starting to get a lot of hits,” Ben says. “We hope to be able to reduce those hits into practice.”
Ben has been combing through these hits in collaboration with the larger DOS team. To date, they have identified several potent hits against the parasite that causes malaria, which today remains an important health scourge and cause of suffering and death in Africa, South America, and Southeast Asia. The timing could not be better for a new discovery since resistance to the best anti-malaria compounds in use today, the artemisinins, is already starting in Western Cambodia and spreading.
Once lead compounds have been found, Ben works closely with the DOS medicinal chemistry team to scout out the terrain of these new molecules to modify the compounds in ways that enhance the way these potential drugs move through the body. For malaria, Ben has teamed with medicinal chemist Richard Heidebrecht whose expertise has been valuable in improving the chemical properties of the lead hits.
Ben, who has spent nearly 20 years of his career in industry, is enthused about these early malaria results, especially since only a small subset of the DOS library has been screened for anti-malaria activity.
Malaria is one of several targeted infectious diseases that the Broad is starting to put through the DOS library. Several compounds have been identified with activity against Trypanosoma cruzi, the parasite that causes Chagas disease, and the parasite that causes leishmaniasis. Again, these hits have surfaced from only a partial screen of the DOS library offerings.
It will be exciting to see what happens when Ben’s team screens the rest of the DOS library and further validates the hits. And the DOS team is still pumping out new compounds. The library is expected to total between 100,000-120,000 by year’s-end.