Small Molecules with Big Dreams

Cell Analysis

Aug 24, 2021 | 6 min read

Drug companies have often had an ambivalence with natural products. On the one hand, natural products provide a rich source of chemically diverse leads for treating human diseases—the best-known example being cholesterol-lowering statins. On the other hand, natural products are often notoriously difficult to source and use in routine target-based screens.

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Dr. Yongjun Dang is inimately familiar with natural products from his post-doctoral research at Johns Hopkins University, and eventual work in Fudan University. In his current role as Director of the newly established Center for Novel Target and Therapeutic Intervention of Chongqing Medical University, he plans to draw from natural product resources to accelerate the field of small molecule research in China.

In our interview, we asked Dr. Dang about his vision for the new center and how he plans to leverage new technologies, such as the iQue^® Advanced Flow Cytometry Platform.

What drove you to study small molecules?

I started my academic career doing basic research in genetics. When I did my postdoctoral research at Johns Hopkins University in 2004, I worked in a laboratory focusing on pharmacology and chemical biology. We worked on repurposing approved drugs and understanding functions of bioactive natural products, and I began exploring mechanisms of small molecules to identify their protein targets, which contributes to translational medicine. Upon my return to Fudan University in 2012, I focused on identification and validation of novel activities of small molecules, especially natural products isolated from marine resources. We also partnered with university affiliated hospitals to accelerate the development of personalized medicine based on small molecules.

Why is small-molecule target identification important for drug discovery?

I always believe that drug discovery should be driven by basic research, through which we can understand functions of different genes, and then, identify possible targets whose activities can be modulated by small molecules, a key step in designing therapeutics. Meanwhile, in China, there is intensive research on natural products, given their important role in drug development. However, the underlying molecular mechanisms for many of the natural products remain unknown, limiting our capabilities for using them as leads for effective drug development. The work on small-molecule targets can help fill the gap, leading to identification of effective compounds for therapeutic use or design of new interventions.

An example is our study at Johns Hopkins on triptolide, a natural product isolated from thunder god vine, a Chinese medicinal herb known for its anti-inflammatory and immunosuppressive activities. It was not until 2011 when we identified the target of triptolide that we were able to explain many of its biological activities. The finding pointed to the potential of triptolide as a molecular probe for studying transcription, and as a new anticancer agent. Continuing the study, I worked on another ingredient of thunder god vine, celastrol, and revealed its weight control mechanism, which will inspire other studies to modulate its target for designing new therapeutics.

What are the challenges in your work?

Identifying targets by working on natural products is very labor and resource-intensive, and requires cross-disciplinary work. You need to isolate, purify and characterize bioactive natural products, chemically modify the compounds to identify their binding targets, and make sure to maintain their bioactivity throughout the process. Then, in verifying the protein targets you also need to work out their biology, reveal the protein structure, and test the binding affinity using in vitro or in vivo studies. We apply chemical, biophysical, biological, and multi-omics tools in our work, always exploring new technologies of different fields.

Studying small molecules by exploring the genetics of disease mechanism is not easy either. Say, you may have discovered certain disease-related genes, but they may only work as diagnostic biomarkers, and are incapable of interventions, thus, become ‘undruggable’. In this sense, understanding gene functions alone may not be sufficient to provide clues for drug targets; we need to identify genes that can be modulated, design or find the workable small molecules, and prove their connections with the genes or proteins, and associations with diseases. Chemical biology is one of the best choices for finding druggable genes that work as valuable targets.

What is your approach to study small molecules?

I focus on identifying the bioactive small molecules first, then, finding their targets and verifying their work mechanisms, which may lead to the design or the discovery of new molecules that can work on the targets, or even new targets. The advantage of this is that it also helps with identifying small molecules working as molecular glue that gathers proteins together and induces protein interactions to disrupt the biology of a disease. An example is rapamycin, an antibiotic typically used as an immune suppressor, which binds two proteins. Based on the identification of its targets, there are recent studies to design new compounds working on the target proteins.

Our approach can also be illustrated by my work on Pateamine A (PatA), a natural compound isolated from marine sponges. It is known to have anticancer and immunosuppressant properties, but the mechanisms were unknown. Through collaboration, we identified its binding target and found that it inhibits eukaryotic translation initiation. The study showed the potential of PatA as a molecular probe and a lead compound for developing anticancer agents. Later, when working with computational biologists to reveal the binding mode of PatA, we found another mechanism, based on which we identified a molecule simpler than PatA.

What is your plan for the new center?

As the key to our approach lies in cross-disciplinary collaboration, I am keen to build a multidisciplinary platform for the new center at Chongqing Medical University, employing tools, including fluorescent probes, computer-aided molecular docking and more.

We’ll have a bioinformatics team, working on clinical big data to identify disease-relevant genes and map out their functions based on our studies on small molecules. Meanwhile, we’ll consolidate existing databases to facilitate studies on small-molecule mechanisms. The drug discovery team will integrate pharmaceutical chemistry, computational biology and artificial intelligence (AI) techniques to work on the synthesis and design of bioactive molecules. AI tools can be used here in predicting protein structures and binding sites, bringing better understanding of the mechanisms. Advanced imaging techniques will also be applied to study crystal structures. These will be complemented by the pharmacology team working on pharmacokinetics and metabolism to verify the mechanisms and effects of identified small molecules. We’ll also apply high-throughput equipment, such as flow cytometry-based iQue^® screening system from Sartorius, which is suitable for cell-based high-throughput screening in immunological field, to accelerate the discovery of bioactive molecules for different diseases. I hope via multidisciplinary integration, we can accelerate the identification of small molecules for drug discovery.