NCI Synthetic Biologics Core

The research conducted within the Synthetic Biologics Core (SBC) Facility has a dual role:

1. Generate chemical biology tools and drug candidates for molecular targets identified by NCI research groups
2. Develop novel effective methods and tools for more effective molecular discovery

Chemical biology tools for studying protein functions have many advantages over applications of genetic approaches for studying protein functions. However, wide use of chemical probes is hampered by the difficulties in their generation and characterization. Because the majority of cancer drivers and proteins regulating immune responses to tumors are considered non-druggable by small molecules, the focus of SBC has been on these high-hanging fruits of drug discovery.

We hypothesize that one of the reasons for our inability to target these difficult targets is that we are not searching in the right part of the chemical universe. The total number of on-the-shelf unique compounds available in the commercial market is on the order of 100 million. This represents only a microscopically small fraction of the drug-like small-molecule space. We have found that the expansion of the accessible part of the chemical universe allows for the discovery of ligands for the most difficult protein targets.

During the past four years, our facility has shifted to mostly computational approaches because they allow for exploration of a very large number of diverse compounds. Virtual screens have recently become one of the primary methods in early leads identification for several reasons:

• Accuracy of docking software, including algorithms evaluating binding energy, has improved significantly
• Sufficient computational resources (clusters, GPUs, cloud computing) have become available
• Significant advances in protein structure determination technologies have been made
• Large virtual libraries of synthesizable compounds have been developed
• AI-based approaches have improved the accuracy of binding predictions

SBC combines modern computational methods with unique computing resources available at NIH to develop new technologies that not only simplify and accelerate the identification of chemical probes but also boost success rates by increasing the accessible part of the chemical universe. SBC is involved in the generation of large databases of synthetically accessible compounds while developing methodologies for mining in these vast databases for ligands of proteins that are of interest to our collaborators. The new methods allow us to screen over 15.5 billion compounds for a single target in several days.